Retroviral protease inhibiting compounds

ABSTRACT

A retroviral protease inhibiting compound of the formula:is disclosed.

This is a division of U.S. patent application Ser. No. 09/619,785, filedJul. 20, 2000, now U.S. Pat. No. 6,531,610 which is a division of U.S.patent application Ser. No. 09/207,881, filed Dec. 8, 1998, now U.S.Pat. No. 6,150,530, which is a division of U.S. patent application Ser.No. 08/418,031, filed Apr. 6, 1995, now U.S. Pat. No. 5,872,052, whichis a division of U.S. patent application Ser. No. 08/158,587, filed Dec.2, 1993, now abandoned, which is a continuation-in-part of U.S. patentapplication Ser. No. 07/998,114, filed Dec. 29 1992, now abandoned,which is a continuation-in-part of U.S. patent application Ser. No.07/777,626, filed Oct. 23, 1991, now abandoned, which is acontinuation-in-part of U.S. patent application Ser. No. 07/746,020,filed Aug. 15, 1991 now abandoned.

This invention was made with Government support under contract numberAI27220 awarded by the National Institute of Allergy and InfectiousDiseases. The Government has certain rights in this invention.

TECHNICAL FIELD

The present invention relates to novel compounds and a composition andmethod for inhibiting retroviral proteases and in particular forinhibiting human immunodeficiency virus (HIV) protease, a compositionand method for treating a retroviral infection and in particular an HIVinfection, processes for making such compounds and syntheticintermediates employed in these processes.

BACKGROUND OF THE INVENTION

Retroviruses are those viruses which utilize a ribonucleic acid (RNA)intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase,reverse transcriptase, during their life cycle. Retroviruses include,but are not limited to, the RNA viruses of the Retroviridae family, andalso the DNA viruses of the Hepadnavirus and Caulimovirus families.Retroviruses cause a variety of disease states in man, animals andplants. Some of the more important retroviruses from a pathologicalstandpoint include human immunodeficiency viruses (HIV-1 and HIV-2),which cause acquired immune deficiency syndrome (AIDS) in man, hepatitisB virus, which causes hepatitis and hepatic carcinomas in man, humanT-cell lymphotrophic viruses I, II, IV and V, which cause human acutecell leukemia, and bovine and feline leukemia viruses which causeleukemia in domestic animals.

Proteases are enzymes which cleave proteins at specific peptide bonds.Many biological functions are controlled or mediated by proteases andtheir complementary protease inhibitors. For example, the protease renincleaves the peptide angiotensinogen to produce the peptide angiotensinI. Angiotensin I is further cleaved by the protease angiotensinconverting enzyme (ACE) to form the hypotensive peptide angiotensin II.Inhibitors of renin and ACE are known to reduce high blood pressure invivo. An inhibitor of a retroviral protease will provide a therapeuticagent for diseases caused by the retrovirus.

The genomes of retroviruses encode a protease that is responsible forthe proteolytic processing of one or more polyprotein precursors such asthe pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988).Retroviral proteases most commonly process the gag precursor into coreproteins, and also process the pol precursor into reverse transciptaseand retroviral protease. In addition, retroviral proteases are sequencespecific. See Pearl, Nature 328 482 (1987).

The correct processing of the precursor polyproteins by the retroviralprotease is necessary for the assembly of infectious virions. It hasbeen shown that in vitro mutagenesis that produces protease-defectivevirus leads to the production of immature core forms which lackinfectivity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al.,Virology 145 280 (1985). Therefore, retroviral protease inhibitionprovides an attractive target for antiviral therapy. See Mitsuya, Nature325 775 (1987).

Current treatments for viral diseases usually involve administration ofcompounds that inhibit viral DNA synthesis. Current treatments for AIDSinvolve administration of compounds such as 3′-azido-3′-deoxythymidine(AZT), 2′,3′-dideoxycytidine (DDC) and 2′,3′-dideoxyinosine (DDI) andcompounds which treat the opportunistic infections caused by theimmunosuppression resulting from HIV infection. None of the current AIDStreatments have proven to be totally effective in treating and/orreversing the disease. In addition, many of the compounds currently usedto treat AIDS cause adverse side effects including low platelet count,renal toxicity and bone marrow cytopenia.

DISCLOSURE OF THE INVENTION

In accordance with the present invention, there are retroviral proteaseinhibiting compounds of the formula A:

wherein R₁ is monosubstituted thiazolyl, monosubstituted oxazolyl,monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein thesubstituent is selected from (i) loweralkyl, (ii) loweralkenyl, (iii)cycloalkyl, (iv) cycloalkylalkyl, (v) cycloalkenyl, (vi)cycloalkenylalkyl, (vii) heterocyclic wherein the heterocyclic isselected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl andpyrazinyl and wherein the heterocyclic is unsubstituted or substitutedwith a substituent selected from halo, loweralkyl, hydroxy, alkoxy andthioalkoxy, (viii) (heterocyclic)alkyl wherein heterocyclic is definedas above, (ix) alkoxyalkyl, (x) thioalkoxyalkyl, (xi) alkylamino, (xii)dialkylamino, (xiii) phenyl wherein the phenyl ring is unsubstituted orsubstituted with a substituent selected from halo, loweralkyl, hydroxy,alkoxy and thioalkoxy, (xiv) phenylalkyl wherein the phenyl ring isunsubstituted or substituted as defined above, (xv) dialkylaminoalkyl,(xvi) alkoxy and (xvii) thioalkoxy;

n is 1, 2 or 3;

R₂ is hydrogen or loweralkyl;

R₃ is loweralkyl;

R₄ and R_(4a) are independently selected from phenyl, thiazolyl andoxazolyl wherein the phenyl, thiazolyl or oxazolyl ring is unsubstitutedor substituted with a substituent selected from (i) halo, (ii)loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy;

R₆ is hydrogen or loweralkyl;

R₇ is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein thethiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted orsubstituted with loweralkyl;

X is hydrogen and Y is —OH or X is —OH and Y is hydrogen, with theproviso that X is hydrogen and Y is —OH when Z is —N(R₈)— and R₇ isunsubstituted and with the proviso that X is hydrogen and Y is —OH whenR₃ is methyl and R₇ is unsubstituted; and

Z is absent, —O—, —S—, —CH₂— or —N(R₈)— wherein R₈ is loweralkyl,cycloalkyl, —OH or —NHR_(8a) wherein R_(8a) is hydrogen, loweralkyl oran N-protecting group; or a pharmaceutically acceptable salt, ester orprodrug thereof.

Preferred compounds of the formula A are those wherein R₁ ismonosubstituted thiazolyl or monosubstituted oxazolyl; n is 1; R₂ ishydrogen; R₄ is phenyl or thiazolyl; R_(4a) is phenyl; R₆ is hydrogenand R₇ is thiazolyl, oxazolyl, isothiazolyl or isoxazolyl.

More preferred compounds of the formula A are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl; n is 1;R₂ is hydrogen; R₄ is phenyl; R_(4a) is phenyl; R₆ is hydrogen and R₇ is5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl.

Even more preferred compounds of the formula A are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is loweralkyl; n is 1; R₂ is hydrogen; R₄ is phenyl;R_(4a) is phenyl; R₆ is hydrogen; R₇ is 5-thiazolyl, 5-oxazolyl,5-isothiazolyl or 5-isoxazolyl; and Z is —O— or —N(R₈)— wherein R₈ isloweralkyl.

Most preferred compounds of the formula A are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is ethyl or isopropyl; n is 1; R₂ is hydrogen; R₃ ismethyl or isopropyl; R₄ is phenyl; R_(4a) is phenyl; R₆ is hydrogen; R₇is 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is—O—.

Most preferred compounds of the formula A are also those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is ethyl or isopropyl; n is 1; R₂ is hydrogen; R₄ isisopropyl; R₄ is phenyl; R_(4a) is phenyl; R₆ is hydrogen; R₇ is5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is—N(R₈)— wherein R₈ is methyl.

Most preferred compounds of the formula A are also those wherein theconfiguration of the carbon atom bearing —CH₂R₄ is “S” and theconfiguration of the carbon bearing X is “S” when X is —OH and theconfiguration of the carbon atom bearing Y is “S” when Y is —OH and theconfiguration of the carbon atom bearing —CH₂(R₅-substituted phenyl) is“S”.

Preferred compounds of the invention are compounds of the formula A1:

wherein R₁ is monosubstituted thiazolyl, monosubstituted oxazolyl,monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein thesubstituent is selected from (i) loweralkyl, (ii) loweralkenyl, (iii)cycloalkyl, (iv) cycloalkylalkyl, (v) cycloalkenyl, (vi)cycloalkenylalkyl, (vii) heterocyclic wherein the heterocyclic isselected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl andpyrazinyl and wherein the heterocyclic is unsubstituted or substitutedwith a substituent selected from halo, loweralkyl, hydroxy, alkoxy andthioalkoxy, (viii) (heterocyclic)alkyl wherein heterocyclic is definedas above, (ix) alkoxyalkyl, (x) thioalkoxyalkyl, (xi) alkylamino, (xii)dialkylamino, (xiii) phenyl wherein the phenyl ring is unsubstituted orsubstituted with a substituent selected from halo, loweralkyl, hydroxy,alkoxy and thioalkoxy, (xiv) phenylalkyl wherein the phenyl ring isunsubstituted or substituted as defined above, (xv) dialkylaminoalkyl,(xvi) alkoxy and (xvii) thioalkoxy;

n is 1, 2 or 3;

R₂ is hydrogen or loweralkyl;

R₃ is loweralkyl;

R₄ is phenyl, thiazolyl or oxazolyl wherein the phenyl, thiazolyl oroxazolyl ring is unsubstituted or substituted with a substituentselected from (i) halo, (ii) loweralkyl, (iii) hydroxy, (iv) alkoxy and(v) thioalkoxy;

R₅ is hydrogen, halo, loweralkyl, hydroxy, alkoxy or thioalkoxy;

R₆ is hydrogen or loweralkyl;

R₇ is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein thethiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted orsubstituted with loweralkyl;

X is hydrogen and Y is —OH or X is —OH and Y is hydrogen, with theproviso that X is hydrogen and Y is —OH when Z is —N(R₈)— and R₇ isunsubstituted and with the proviso that X is hydrogen and Y is —OH whenR₃ is methyl and R₇ is unsubstituted;

Z is absent, —O—, —S—, —CH₂— or —N(R₈)— wherein R₈ is loweralkyl,cycloalkyl, —OH or —NHR_(8a) wherein R_(8a) is hydrogen, loweralkyl oran N-protecting group; or a pharmaceutically acceptable salt, ester orprodrug thereof.

Preferred compounds of the formula A1 are those wherein R₁ ismonosubstituted thiazolyl or monosubstituted oxazolyl; n is 1; R₂ ishydrogen; R₄ is phenyl or thiazolyl; R₅ is hydrogen; R₆ is hydrogen andR₇ is thiazolyl, oxazolyl, isothiazolyl or isoxazolyl.

More preferred compounds of the formula A1 are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl; n is 1;R₂ is hydrogen; R₄ is phenyl; R₅ is hydrogen; R₆ is hydrogen and R₇ is5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl.

Even more preferred compounds of the formula A1 are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is loweralkyl; n is 1; R₂ is hydrogen; R₄ is phenyl; R₅is hydrogen; R₆ is hydrogen; R₇ is 5-thiazolyl, 5-oxazolyl,5-isothiazolyl or 5-isoxazolyl; and Z is —O— or —N(R₈)— wherein R₈ isloweralkyl.

Most preferred compounds of the formula A1 are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is ethyl or isopropyl; n is 1; R₂ is hydrogen; R₃ ismethyl or isopropyl; R₄ is phenyl; R₅ is hydrogen; R₆ is hydrogen; R₇ is5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is —O—.

Most preferred compounds of the formula A1 are also those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is ethyl or isopropyl; n is 1; R₂ is hydrogen; R₃ isisopropyl; R₄ is phenyl; R₅ is hydrogen; R₆ is hydrogen; R₇ is5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is—N(R₈)— wherein R₈ is methyl.

Most preferred compounds of the formula A1 are also those wherein X ishydrogen and Y is —OH.

Most preferred compounds of the formula A1 are also those wherein theconfiguration of the carbon atom bearing —CH₂R₄ is “S” and theconfiguration of the carbon bearing X is “S” when X is —OH and theconfiguration of the carbon atom bearing Y is “S” when Y is —OH and theconfiguration of the carbon atom bearing —CH₂(R₅-substituted phenyl) is“S”.

In accordance with the present invention, there are also retroviralprotease inhibiting compounds of the formula A2:

wherein R₁ is monosubstituted thiazolyl, monosubstituted oxazolyl,monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein thesubstituent is selected from (i) loweralkyl, (ii) loweralkenyl, (iii)cycloalkyl, (iv) cycloalkylalkyl, (v) cycloalkenyl, (vi)cycloalkenylalkyl, (vii) heterocyclic wherein the heterocyclic isselected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl andpyrazinyl and wherein the heterocyclic is unsubstituted or substitutedwith a substituent selected from halo, loweralkyl, hydroxy, alkoxy andthioalkoxy, (viii) (heterocyclic)alkyl wherein heterocyclic is definedas above, (ix) alkoxyalkyl, (x) thioalkoxyalkyl, (xi) alkylamino, (xii)dialkylamino, (xiii) phenyl wherein the phenyl ring is unsubstituted orsubstituted with a substituent selected from halo, loweralkyl, hydroxy,alkoxy and thioalkoxy, (xiv) phenylalkyl wherein the phenyl ring isunsubstituted or substituted as defined above, (xv) dialkylaminoalkyl,(xvi) alkoxy and (xvii) thioalkoxy;

n is 1, 2 or 3;

R₂ is hydrogen or loweralkyl;

R₃ is loweralkyl;

R₄ and R_(4a) are independently selected from phenyl, thiazolyl andoxazolyl wherein the phenyl, thiazolyl or oxazolyl ring is unsubstitutedor substituted with a substituent selected from (i) halo, (ii)loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy;

R₆ is hydrogen or loweralkyl;

R₇ is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein thethiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted orsubstituted with loweralkyl;

X is —OH and Y is —OH; and

Z is absent, —O—, —S—, —CH₂— or —N(R₈)— wherein R₈ is loweralkyl,cycloalkyl, —OH or —NHR_(8a) wherein R_(8a) is hydrogen, loweralkyl oran N-protecting group; or a pharmaceutically acceptable salt, ester orprodrug thereof.

Preferred compounds of the formula A2 are those wherein R₁ ismonosubstituted thiazolyl or monosubstituted oxazolyl; n is 1; R₂ ishydrogen; R₄ is phenyl or thiazolyl; R_(4a) is phenyl; R₆ is hydrogenand R₇ is thiazolyl, oxazolyl, isothiazolyl or isoxazolyl.

More preferred compounds of the formula A2 are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl; n is 1;R₂ is hydrogen; R₄ is phenyl; R_(4a) is phenyl; R₆ is hydrogen and R₇ is5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl.

Even more preferred compounds of the formula A2 are those wherein R₁ is2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl whereinthe substituent is loweralkyl; n is 1; R₂ is hydrogen; R₄ is phenyl;R_(4a) is phenyl; R₆ is hydrogen; R₇ is 5-thiazolyl, 5-oxazolyl,5-isothiazolyl or 5-isoxazolyl; and Z is —O— or —N(R₈)— wherein R₈ isloweralkyl.

Preferred compounds of the formula A2 are also those wherein theconfiguration of the carbon atom bearing —CH₂R₄ is “S” and theconfiguration of the carbon atom bearing —CH₂(R₅-substituted phenyl) is“S”.

The compounds of the invention comprise asymmetrically substitutedcenters (i.e., asymmetrically substituted carbon atoms). The presentinvention is intended to include all stereoiosomeric forms of thecompounds, including racemic mixtures, mixtures of diastereomers, aswell as single diastereomers of the compounds of the invention. Theterms “S” and “R” configuration are as defined by the IUPAC 1974Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.Chem. (1976) 45, 13-30.

The terms “Val” and “Ala” as used herein refer to valine and alanine,respectively. Unless otherwise noted, when “Val” and “Ala” are usedherein they refer to the L-isomer. In general, the amino acidabbreviations used herein follow the IUPAC-IUB Joint Commission onBiochemical Nomenclature for amino acids and peptides (Eur. J. Biochem.1984, 158, 9-31).

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undersirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, “Protective Groups In Organic Synthesis,” (JohnWiley & Sons, New York (1981)), which is hereby incorporated byreference. N-protecting groups comprise acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) andbenzyloxycarbonyl (Cbz).

The term “O-protecting group” as used herein refers to a substituentwhich protects hydroxyl groups against undesirable reactions duringsynthetic procedures such as those O-protecting groups disclosed inGreene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons,New York (1981)). O-protecting groups comprise substituted methylethers, for example, methoxymethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, t-butyl, benzyland triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers,for example, 2,2,2-trichloroethyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; andesters prepared by reacting the hydroxyl group with a carboxylic acid,for example, acetate, propionate, benzoate and the like.

The term “loweralkyl” as used herein refers to straight or branchedchain alkyl radicals containing from 1 to 6 carbon atoms including, butnot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl and the like.

The term “loweralkenyl” as used herein refers to a straight or branchedchain alkyl radical containing from 2 to 6 carbon atoms and also havingone carbon-carbon double bond including, but not limited to, vinyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl andthe like.

The term “phenyl” as used herein refers to a phenyl group which isunsubstituted or substituted with a substituent selected fromloweralkyl, alkoxy, thioalkoxy, hydroxy and halo.

The term “phenylalkyl” as used herein refers to an phenyl group appendedto a loweralkyl radical including, but not limited to, benzyl,4-hydroxybenzyl, 4-chlorobenzyl, 1-naphthylmethyl and the like.

The term “alkylamino” as used herein refers to a loweralkyl radicalappended to an —NH radical.

The term “cycloalkyl” as used herein refers to an aliphatic ring having3 to 7 carbon atoms including, but not limited to, cyclopropyl,cyclopentyl, cyclohexyl and the like. A preferred cycloalkyl group iscyclopropyl

The term “cycloalkylalkyl” as used herein refers to a cycloalkyl groupappended to a loweralkyl radical, including but not limited tocyclohexylmethyl.

The term “cycloalkenyl” as used herein refers to to an aliphatic ringhaving 5 to 7 carbon atoms and also having one carbon-carbon double bondincluding, but not limited to, cyclopentenyl, cyclohexenyl and the like.

The term “cycloalkenyalkyl” as used herein refers to a cycloalkenylgroup appended to a loweralkyl radical including, but not limited to,cyclopentenylmethyl, cyclohexenylmethyl and the like.

The terms “alkoxy” and “thioalkoxy” as used herein refer to R₁₅O— andR₁₅S—, respectively, wherein R₁₅ is a loweralkyl group or benzyl.

The term “alkoxyalkyl” as used herein refers to an alkoxy group appendedto a loweralkyl radical.

The term “thioalkoxyalkyl” as used herein refers to a thioalkoxy groupappended to a loweralkyl radical.

The term “dialkylamino” as used herein refers to —NR₁₆R₁₇ wherein R₁₆and R₁₇ are independently selected from loweralkyl groups.

The term “dialkylaminoalkyl” as used herein refers to —NR₁₈R₁₉ which isappended to a loweralkyl radical wherein R₁₈ and R₁₉ are independentlyselected from loweralkyl.

The term “halo” or “halogen” as used herein refers to —Cl, —Br, —I or—F.

The term “heterocyclic” as used herein refers to a heterocyclic groupselected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl andpyrazinyl and wherein the heterocyclic is unsubstituted or substitutedwith a substituent selected from halo, loweralkyl, hydroxy, alkoxy andthioalkoxy.

The term “(heterocyclic)alkyl” as used herein refers to a heterocyclicgroup appended to a loweralkyl radical including, but not limited to,pyrrolidinylmethyl and morpholinylmethyl.

The term “activated ester derivative” as used herein refer to acidhalides such as acid chlorides, and activated esters including, but notlimited to, formic and acetic acid derived anhydrides, anhydridesderived from alkoxycarbonyl halides such as isobutyloxycarbonylchlorideand the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimidederived esters, N-hydroxybenzotriazole derived esters,N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,2,4,5-trichlorophenol derived esters and the like.

In the compounds of the invention, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds. As used herein, the term “stable compound” refers to acompound that is sufficiently stable to survive isolation to a usefuldegree of purity from a reaction mixture and formulation into atherapeutic dosage form suitable for administration.

Preferred compounds of the invention are selected from the groupconsisting of:

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-2-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-2-(N-(N-((2-(4-morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)-1,6-carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;and

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;or a pharmaceutically acceptable salt, ester or prodrug thereof.

Compounds useful as intermediates for the preparation of the compound offormula A and A1 include the compound of the formula A3:

wherein R₄ and R_(4a) are independently selected from phenyl, thiazolyland oxazolyl wherein the phenyl, thiazolyl or oxazolyl ring isunsubstituted or substituted with a substituent selected from (i) halo,(ii) loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy; and R*is phenyl, halo-substituted phenyl, dihalo-substituted phenyl,alkoxy-substituted phenyl, loweralkyl-substituted phenyl,bis-trifluromethyl-substituted phenyl or naphthyl or loweralkyl; or anacid addition salt thereof.

Preferred intermediates are compounds of the formula A4:

wherein R₄ and R_(4a) are independently selected from phenyl, thiazolyland oxazolyl wherein the phenyl, thiazolyl or oxazolyl ring isunsubstituted or substituted with a substituent selected from (i) halo,(ii) loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy; and R*is phenyl, halo-substituted phenyl, dihalo-substituted phenyl,alkoxy-substituted phenyl, loweralkyl-substituted phenyl,bis-trifluromethyl-substituted phenyl or naphthyl or loweralkyl; or anacid addition salt thereof.

Preferred compounds of the formula A4 are those wherein R_(4a) is phenyland R* is phenyl. Most preferred compounds of the formula A4 are thosewherein R₄ and R_(4a) are phenyl and R* is phenyl.

The compounds of the invention can be prepared as shown in Schemes 1-9.As outlined in Scheme 1, coupling of protected α-aminoaldehyde Ia and Ib(R₃₀ is loweralkyl or benzyl) with VCI₃(tetrahydrofuran)₃ and Znproduces a mixture of diols, out of which compounds II and III can beisolated. Hydrolysis of II and III with barium hydroxide leads,respectively, to diaminodiols IV and V. Alternately, treatment of IIwith α-acetoxyisobutyryl bromide in acetonitrile leads to compound VI,which upon hydrolysis with barium hydroxide, produces diaminodiol VII.In a preferred embodiment, R₄ and R_(4a) are each phenyl and the firstreaction in Scheme 1 is a dimerization.

As outlined in Scheme 2, treatment of compound II withα-acetoxyisobutyryl bromide in hexane/dichloromethane producesbromoacetate VIII. Hydrolysis of VIII with concommitant cyclizationproduces epoxide IX, which is reduced with sodium borohydride andtrifluoroacetic acid to produce compound X. Barium hydroxide hydrolysisof X leads to diamine XI.

As outlined in Scheme 3, acylation of the enolate derived from compoundXII with ethyl chloroformate gives compound XIII. Subsequent alkylationof the enolate prepared from XIII provides compound XIV (R_(4a) isthiazolyl), which is hydrolyzed and decarboxylated to lactone XV.Hydrolysis of XV and protection of the hydroxyl group leads to compoundXVI, which, upon treatment with diphenylphosphoryl azide undergoes aCurtius rearrangement. The intermediate isocyanate is trapped withbenzyl alcohol to produce compound XVII. Desilylation of XVII withtetrabutylammonium fluoride provides compound XVIII, which isdeprotected with HBr to give diamine XIX.

In a preferred embodiment of the process shown in Scheme 3, R₄ isphenyl.

As outlined in Scheme 4, compound XX (R₃ is loweralkyl) is converted toisocyanate XXI by treatment with phosgene. Alternatively, treatment ofXX with 4-nitrophenyl chloroformate produces carbamate XXII.Condensation of either XXI or XXII with compound XXIII wherein Z is O, Sor N(R₈), with catalytic 4-dimethylaminopyridine as needed, providescompound XXIV. Lithium hydroxide hydrolysis of XXIV produces compoundXXV. In a preferred embodiment of the process shown in Scheme 4, n is 1.

As outlined in Scheme 5, compound XXVIII, which represents diamines IV,V, VII, XI and XIX, is acylated with an activated derivative of XXVIhaving the formula (R₆)(R₇)CHOC(O)OL wherein L is an activating groupfor the acylation reaction such as p-nitrophenyl, phenyl,N-succinimidyl, N-phthalimidyl, N-benzotriazolyl,N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl and the like(for example, XXVII, which is prepared by reacting XXVI with4-nitrophenyl chloroformate) to provide a mixture of compounds XXIXa andXXIXb or an acid addition salt thereof. Coupling of XXIXa or XXIXb tocompound XXX by treatment with a carbodiimide (or by reaction with anactivated ester of XXX) produces compound XXXIa or XXXIb, respectively.In a preferred embodiment of the process shown in Scheme 5, n is 1, R₄and R_(4a) are each phenyl, X is H and Y is OH.

As outlined in Scheme 6A, treatment of diamine XI with a boronic acid(preferably, phenylboronic acid) or a boroxine produces compound XXXII,which is selectively acylated with an activated derivative of XXVIhaving the formula (R₆)(R₇)CHOC(O)OL within L is an activating group forthe acylation reaction such as p-nitrophenyl, phenyl, N-succinimidyl,N-phthalimidyl, N-benzotriazolyl, N-5-norbornene-2,3-carboxamidyl or2,4,5-trichlorophenyl and the like (for example, XXVII) to providecompound XXXIIIa or an acid addition salt thereof. Carbodiimide-mediatedcoupling of XXXIIIa to compound XXX (or reaction of XXXIIIa with anactivated ester of XXX) leads to compound XXXIVa. In a preferredembodiment of the process shown in Scheme 6A, n is 1, R₄ and R_(4a) areeach phenyl and R* is phenyl.

Alternatively, compound XXXII can be acylated with compound XXX (or anactivated ester thereof) to provide compound XXXIIIb or an acid additionsalt thereof. Acylation of compound XXXIIIIb with an activatedderivative of XXVI having the formula (R₆)(R₇)CHOC(O)OL wherein L is anactivating group for the acylation reaction such as p-nitrophenyl,phenyl, N-succinimidyl, N-phthalimidyl, N-benzotriazolyl,N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl and the like(for example, XXVII) provides compound XXXIVb.

Scheme 6B outlines an alternative preparation of XXXIIIa or XXXIIIb.Reaction of compound XI with (i) two equivalents of B(OR**)₃ wherein R**is loweralkyl (preferably, isopropyl) or (ii) two equivalents ofB(R***)₃ wherein R*** is halo (preferably, fluoro) and four equivalentsof an amine such as triethylamine in an inert solvent such astetrahydrofuran, followed by reaction with an activated derivative ofXXVI having the formula (R₆)(R₇)CHOC(O)OL wherein L is an activatinggroup for the acylation reaction such as p-nitrophenyl, phenyl,N-succinimidyl, N-phthalimidyl, N-benzotriazolyl,N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl and the like(for example, XXVII), gives compound XXXIIIa or an acid addition saltthereof. Similarly, reaction of compound XI with two equivalents ofB(OR**)₃ wherein R** is loweralkyl (preferably, isopropyl) or twoequivalents of B(R***)₃ wherein R*** is halo (preferably, fluoro),followed by reaction with compound XXX (or an activated ester derivativethereof), gives compound XXXIIIb or an acid addition salt thereof. Inthe preferred embodiment of the process shown in Scheme 6B, n is 1, R₄and R_(4a) are each phenyl and R** is isopropyl or R*** is fluoro.

Scheme 6C outlines an alternative preparation of XXXIVa and XXXIVb.Reaction of compound XI with two molar equivalents of Ti(OR****)₄wherein R₄ is loweralkyl (preferably, isopropyl), followed by reactionwith an activated derivative of XXVI having the formula(R₆)(R₇)CHOC(O)OL wherein L is an activating group for the acylationreaction such as p-nitrophenyl, phenyl, N-succinimidyl, N-phthalimidyl,N-benzotriazolyl, N-5-norbornene-2,3-carboxamidyl or2,4,5-trichlorophenyl and the like (for example, XXVII), providescompound XLII or an acid addition salt thereof. Reaction of compoundXLII with compound XXX (or an activated ester derivative thereof) givescompound XXXIVb. Similarly, reaction of compound XI with two molarequivalents of Ti(OR****)₄ wherein R₄ is loweralkyl (preferably,isopropyl), followed by reaction with compound XXX (or an activatedester derivative thereof), provides compound XLIII or an acid additionsalt thereof. Reaction of compound XLIII with an activated derivative ofXXVI having the formula (R₆)(R₇)CHOC(O)OL wherein L is an activatinggroup for the acylation reaction such as p-nitrophenyl, phenyl,N-succinimidyl, N-phthalimidyl, N-benzotriazolyl,N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl and the like(for example, XXVII) gives compound XXXIVa. In the preferred embodimentof the process shown in Scheme 6C, n is 1, R₄ and R_(4a) are each phenyland R**** is isopropyl.

Scheme 7 shows an alternative preparation of diaminomono-ol XI. Reactionof ketonitrile XXXV with Grignard reagent R_(4a)CH₂MgX providesketoenamine XXXVI. Reaction of the ketoenamine with NaBH₄CH₃SO₃H,followed by reaction of the resulting intermediate (without isolation)with NaBH₄/CF₃CO₂H, provides XXXVII. Hydrogenation of the benzyl groupsgives XI. Alternatively, protection of the free amino group of XXXVII asthe t-butyloxycarbonylamino group, followed by hydrogenation of thebenzyl groups, gives XXXVIII. In a preferred embodiment, R₄ and R_(4a)are each phenyl.

Scheme 8 shows an alternative preparation of XXXVIII. N-protection ofXXXVI gives XXXIX. Reaction of XXXIX with borane-tetrahydrofurancomplex, followed by reaction of the resulting product with LiAlH₄ orKBH₄, provides the N,N-dibenzyl precursor to XXXVIII.

Scheme 9 shows how the selectively protected diamine XXXIX can be usedto prepare compounds of the invention XL and XLI.

The following examples will serve to further illustrate the preparationof the novel compounds of the invention.

EXAMPLE 1 A. N-(((Benzyl)oxy)carbonyl)-L-phenylalaninal

A solution of 24.5 ml of anhydrous dimethyl sulfoxide in 870 ml ofanhydrous dichloromethane was cooled under N₂ atmosphere to −60° C. andtreated over a period of 15 min with 131 ml of a 2 M solution of oxalylchloride in dichloromethane in order that the internal temperatureremained below −50° C. After addition, the solution was stirred at −60°C. for 15 min and treated over a period of 20 min with a solution of 50g (0.175 mol) of N-(((benzyl)oxy)-carbonyl)-L-phenylalaninol in 200 mlof dichloromethane The resulting solution was stirred at −60° C. for 1h, then treated over a period of 15 min with 97 ml of triethylamine inorder that the internal temperature remained below −50° C. Afteraddition the solution was stirred at −60° C. for 15 min, then, with thecooling bath in place, was treated rapidly (over a period of 1 min) witha solution of 163 g of citric acid in 550 ml of water. The resultingslurry was stirred vigorously for 10 min, allowed to warm, diluted to 1liter with water, and separated. The organic layer was washed with 700ml of water followed by a mixture of 550 ml of water and 150 ml ofsaturated aqueous NaHCO₃, dried over MgSO₄, and concentrated in vacuo at20° C. to give the crude desired compound as a light yellow solid.

B.(2S,3R,4R,5S)-2,5-bis-(N-(((Benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-dihenylhexaneand(2S,3S,4S,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A suspension of 78.5 g of VCI₃′(tetrahydrofuran)3 and 16 g of zinc dustin 400 ml of dry dichloromethane was stirred under N₂ atmosphere for 1 hat 25° C. A solution of 0.175 mol ofN-(((benzyl)oxy)carbonyl)-L-phenylalaninal in 200 ml of dichloromethanewas then added in one portion, and the resulting mixture was stirred atambient temperature under N₂ atmosphere for 16 h. The resulting mixturewas added to 500 ml of 1 M aqueous HCl, diluted with 500 ml of hotchloroform, and shaked vigorously for 2 min. The layers were separated,and the organic layer was washed with 1 M aqueous HCl and separated.Filtration of the organic phase provided the crude desired product as asolid residue. The residue was slurried in 1.25 liters of acetone,treated with 5 ml of concentrated H₂SO₄, and stirred for 16 h at ambienttemperature. The resulting mixture was filtered, and the residue(residue A) was washed with 50 ml of acetone. The combined filtrate wasconcentrated to a volume of 250 ml, diluted with 1000 ml ofdichloromethane, washed three times with water and once with saturatedbrine, dried over MgSO₄, and concentrated to give a viscous oil. The oilwas taken up in 1000 ml of 1 M HCl in methanol (prepared from 71 ml ofacetyl chloride and 1000 ml of methanol) and stirred at ambienttemperature for 2 h. The resulting precipitate was filtered, washed withmethanol, and air-dried on the filter to provide 26.7 g of the desiredcompound as a white solid. The filtrate was concentrated and filtered togive a second crop (8.3 g) of(2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.¹H NMR (d₆-DMSO) δ 2.59 (dd, J=13, 5 Hz, 2H), 2.74 (dd, J=13, 9 Hz, 2H),3.26 (br, 2H), 4.19 (m, 2H), 4.54 (m, 2H), 4.92 (m, 4H), 6.82 (d, J=9Hz, 2H), 7.0-7.35 (m, 20H). Mass spectrum: (M+H)⁺=569.

Residue A (above, 2.65 g) was suspended in 75 ml of tetrahydrofuran(THF) and 75 ml of 1 M aqueous HCl and heated at reflux for 24 h. Afterconcentration of the resulting solution in vacuo, the residue was takenup in 10% methanol in chloroform, washed two times with water, driedover Na₂SO₄, and concentrated in vacuo to provide(2S,3S,4S,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexaneas a white solid. ¹H NMR (d₆-DMSO) δ 2.64 (m, 2H), 3.04 (m, 2H), 3.49(m, 2H), 3.78 (m, 2H), 4.70 (d, J=7 Hz, 2H), 4.93 (AA′, 4H), 7.1-7.4 (m,20H). Mass spectrum: (M+H)⁺=569.

C.(2S,3R,4S,5S)-3-Acetoxy-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3-bromo-1,6-diphenylhexane

A suspension of 25 g (44 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexanein 500 ml of 2:1 dichloromethane/hexane was treated with 23 g ofα-acetoxyisobutyryl bromide. The resulting mixture was stirred atambient temperature until the reaction clarified, washed with two 200 mlportions of saturated aqueous NaHCO₃, dried over MgSO₄, and concentratedin vacuo to give 30.8 g of the crude desired compound. A portion waspurified by silica gel chromatography using 9:1 dichloromethane:ethylacetate to provide the pure desired compound as a white solid. ¹H NMR(CDCl₃) δ 2.21 (s, 3H), 2.62 (dd, J=13, 11 Hz, 1H), 2.75 (d, J=7 Hz,2H), 2.95 (br d, J=15 Hz, 1H), 4.03 (br t, J=10 Hz, 1 h), 4.40 (br d,J=10 Hz, 1H), 4.6-5.0 (m, 6H), 5.12 (br d, J=13 Hz, 1H), 5.33 (br d,J=11 Hz, 1H), 7.0-7.4 (m, 10H). Mass spectrum: (M+NH₄)⁺=690, 692.

D.(2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexane

A solution of 35.56 g (52.8 mmol) of(2S,3R,4S,5S)-3-acetoxy-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3-bromo-1,6-diphenylhexanein 375 ml of dioxane was treated with 255 ml of 1N aqueous sodiumhydroxide and stirred at ambient temperature for 16 h, during which thedesired compound precipitated. The resulting mixture was filtered, andthe residue was washed with water and dried to provide 22.23 g (76%) ofthe desired compound as a white solid. ¹H NMR (CDCl₃) δ 2.7-2.9 (m, 6H),3.9-4.0 (m, 2H), 4.6-4.7 (m, 2H), 5.03 (m, 4H), 7.1-7.4 (m, 10H).

E.(2S,3S,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-1.6-diphenyl-3-hydroxyhexane

A mixture of 39.2 g (71.2 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexanein 600 ml of THF was treated under N₂ atmosphere with 13 g (0.36 mol) ofsodium borohydride. The resulting mixture was treated dropwise with 27.7ml (0.36 mol) of trifluoroacetic acid. After being stirred for 3.5 h atambient temperature, the resulting mixture was quenched with 1N aqueousHCl, diluted with water, and stirred for 16 h. The resulting mixture wasfiltered, washed with water, and dried to provide 22.85 g (58%) of thedesired compound as a white solid.

F. (2S,3S,5S)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane

A suspension of 32 g of the crude resultant compound of Example 1E and55.5 g (176 mmol) of barium hydroxide octahydrate in 400 ml of1,4-dioxane and 400 ml of water was heated at reflux for 4 h. Theresulting mixture was filtered, and the residue was rinsed with dioxane.The combined filtrates were concentrated to a volume of approximately200 ml and extracted with four 400 ml portions of chloroform. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography using first 2% isopropylamine in chloroform and then 2%isopropylamine/2% methanol in chloroform to provide 10.1 g (81%) of thepure desired compound as a white solid. ¹H NMR (CDCl₃) δ 1.54 (dt, J=14,10 Hz, 1H), 1.67 (dt, J=14, 3 Hz, 1H), 2.50 (dd, J=13, 8 Hz, 1H), 2.58(dd, J=13, 8 Hz, 1H), 2.8 (m, 2H), 2.91 (dd, J=13, 5 Hz, 1H), 3.10 (m,1H), 3.72 (ddd, J=11, 3, 2 Hz, 1H), 7.1-7.4 (m, 10H). Mass spectrum:(M+H)⁺=285.

G.(4S,6S,1′S)-6-(1-Amino-2-phenylethyl)-4-benzyl-2-phenyl-3-aza-2-bora-1-oxacyclohexane

A solution of 131 g (460 mmol) of(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane in 1.2 L of toluenewas treated under N₂ atmosphere with 56.16 g (460 mmol) of phenylboricacid. The resulting solution was heated at reflux (bath temperature 135°C.) and water azeotropically removed with the aid of a Dean Stark trapuntil the distillate was clear and the theoretical amount of water (15.6ml) was collected (ca 1.5 h). After, being allowed to cool, the solutionwas concentrated in vacuo to provide 176 g of the crude desired compoundas a resin. H¹NMR (CDCl₃) δ 7.59 (m, 2H), 7.47-7.07 (m, 13H, 3.92 (m,1H), 3.78 (s br, 1H), 3.52 (m, 1), 3.50 (m, 2H), 2.87 (dd, 1H, J=13.5,5.7 Hz), 2.72 (m, 1H), 2.58 (dd, 1H, J=13.5, 8.7 Hz), 1.92 (m, 1H), 1.68(m, 1H), 1.60-1.30 (s-very broad, 2H). CIMS m/z 371 (M+H).

H. Thioformamide

To a cooled (0° C.) 2 L three neck round bottom flask equipped with anoverhead stirrer charged with a solution of formamide (30.5 mL, 0.76mol) in 1 L of diethyl ether was added 89 g (0.19 mol) of phosphorouspentasulfide in small portions. The reaction mixture was allowed to warmto ambient temperature, stirred for 2 h, filtered, and concentrated invacuo to afford thioformamide as a yellow offensive smelling oil whichwas used without purification.

I. Ethyl 2-Chloro-2-formylacetate

To a three neck 2 L round bottom flask charged with potassium t-butoxide(0.5 mol, 500 mL of a 1 M solution in THF) and 500 mL of dry THF cooledto 0° C. was added dropwise from an addition funnel a solution of ethylchloroacetate (0.5 mol, 53.5 mL) and ethyl formate (0.5 mol, 40.4 mL),in 200 mL of THF over 3 hours. After completion of addition, thereaction mixture was stirred for 1 hour and allowed to stand overnight.The resulting solid was diluted with diethyl ether and cooled in an icebath. Then, the pH was lowered to approximately 3 using 6N HCl. Theorganic phase was separated, and the aqueous layer was washed 3 timeswith diethyl ether. The combined ethereal portions were dried overNaSO₄, and concentrated in vacuo. The crude desired compound was storedat −30° C. and used without further purification.

J. Ethyl Thiazole-5-carboxylate

To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl2-chloro-2-formylacetate. The reaction was heated at reflux for 2 hours.The solvent was removed in vacuo, and the residue was purified bychromatography (SiO₂, 6 cm o.d. column, 100% CHCl₃, R_(f)=0.25) toprovide 11.6 g (60%) of the desired compound as a light yellow oil. NMR(CDCl₃) δ 1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95(s, 1H).

K. 5-(Hydroxymethyl)thiazole

To a precooled (ice bath) three neck 500 mL flask containing lithiumaluminum hydride (76 mmol) in 250 mL of THF was added ethylthiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwiseover 1.5 hours to avoid excess foaming. The reaction was stirred for anadditional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of15% NaOH, and 8.7 mL of water. The solid salts were filtered, and thefiltrate set aside. The crude salts were heated at reflux in 100 mL ofethyl acetate for 30 min. The resulting mixture was filtered, and thetwo filtrates were combined, dried over Na₂SO₄, and concentrated invacuo. The product was purified by silica gel chromatography elutingsequentially with 0%-2%-4% methanol in chloroform, to provide thedesired compound, Rf=0.3 (4% methanol in chloroform), which solidifiedupon standing in 75% yield. NMR (CDCl₃) δ 4.92 (s, 2H), 7.78 (s, 1H),8.77 (s, 1H). Mass spectrum: (M+H)⁺=116.

L. ((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate

A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excessN-methyl morpholine in 100 ml of methylene chloride was cooled to 0° C.and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. Afterbeing stirred for 1 h, the reaction mixture was diluted with CHCl₃,washed successively with 1N HCl, saturated aqueous NaHCO₃, and saturatedbrine, dried over NaSO₄, and concentrated in vacuo. The residue waspurified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl₃, Rf=0.5 in4% MeOH/CHCl₃) to yield 5.9 g (78%) of the desired compound as a yellowsolid. NMR (CDCl₃) δ 5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s,1H), 8.29 (dt, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)⁺=281.

M.(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-2-Amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 500 mg (1.76 mmol) of(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane and 480 mg (1.71mmol) of ((5-thiazolyl)methyl)(4-nitrophenyl)carbonate in 20 ml of THFwas stirred at ambient temperature for 4 h. After removal of the solventin vacuo, the residue was purified by silica gel chromatography usingfirst 2% then 5% methanol in chloroform to provide a mixture of the twodesired compounds. Silica gel chromatography of the mixture using agradient of 0-1-2% methanol in 93:2 isopropylamine:chloroform provided110 mg (16%) of(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane(R_(f) 0.48, 96:2:2 chloroform:methanol:isopropylamine) and 185 mg (28%)of(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane(R_(f) 0.44, 96:2:2 chloroform:methanol:isopropylamine).

(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane:NMR (CDCl₃) δ 1.3-1.6 (m, 2H), 2.40 (dd, J=14, 8 Hz, 1H), 2.78 (dd, J=5Hz, 1H), 2.88 (d, J=7 Hz, 2H), 3.01 (m, 1H), 3.72 (br q, 1H), 3.81 (brd, J=10 Hz, 1H), 5.28 (s, 2H), 5.34 (br d, J=9 Hz, 1H), 7.07 (br d, J=7Hz, 2H), 7.15-7.35 (m, 8H), 7.87 (s, 1H), 8.80 (s, 1H). Mass spectrum:(M+H)⁺=426.

(2S,3S,5S)-2-Amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane:NMR (CDCl₃) δ 1.55 (dt, J=14, 8 Hz, 1H), 1.74 (m, 1H), 2.44 (dd, J=15, 1Hz, 1H), 2.75-3.0 (m, 4H), 3.44 (m, 1H), 4.00 (br t, 1H), 5.28 (m,3H),7.1-7.4 (m, 10H), 7.86 (s, 1H), 8.80 (s, 1H). Mass spectrum: (M+H)⁺=426.

N.(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 40 mmol of crude(4S,6S,1′S)-6-(1-amino-2-phenylethyl)-4-benzyl-2-phenyl-3-aza-2-bora-1-oxacyclohexanein 700 ml of anhydrous THF was cooled to −40° C. and treated dropwiseover a period of 1 h with a solution of 7.83 g (27.9 mmol) of((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 300 ml of dry THF. Theresulting solution was allowed to warm to 0° C. for 3 h, then to ambienttemperature for 16 h. The solvent was removed in vacuo, and the residuewas taken up in 700 ml of ethyl acetate, washed with three 150 mlportions of 1N aqueous NaOH and one 150 ml portion of brine. The organicphase was dried over Na₂SO₄ and concentrated in vacuo. Purification ofthe residue by silica gel chromatography using methanol/chloroformmixtures provided the desired compound mixed with its regioisomer. Asecond chromatography using 1-3% isopropylamine in chloroform provided5.21 g of the desired compound which solidified upon standing.

O. 2-Methylpropane-thioamide

A suspension of 100 g (1.15 mol) of isobutyramide in 4 L of diethylether was stirred vigorously and treated in portions with 51 g (0.115mol) of P₄S₁₀. The resulting mixture was stirred at ambient temperaturefor 2 h, filtered, and concentrated in vacuo to provide 94.2 g (80%) ofthe crude desired compound. ¹H NMR (DMSO-d₆) δ 1.08 (d, J=7 Hz, 6H),2.78 (heptet, J=7 Hz, 1H), 9.06 (br, 1H), 9.30 (br, 1H). Mass spectrum:(M+H)⁺104.

P. 4-(Chloromethyl)-2-isopropylthiazole Hydrochloride

A mixture of 94.0 g (0.91 mol) of 2-methylpropane-thioamide, 115.7 g(0.91 mol) of 1,3-dichloroacetone, and 109.7 g (0.91 mol) of MgSO₄ in1.6 liters of acetone was heated at reflux for 3.5 h. The resultingmixture was allowed to cool, filtered, and the solvent was removed invacuo to provide the crude desired compound as a yellow oil. ¹H NMR(DMSO-d₆) δ 1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 4.78 (s,2H), 7.61 (s, 1H). Mass spectrum: (M+H)⁺=176.

Q. 2-Isopropyl-4-(((N-methyl)amino)methyl)thiazole

A solution of 40 g of 4-(chloromethyl)-2-isopropylthiazole hydrochloridein 100 ml of water was added dropwise with stirring to 400 ml of 40%aqueous methylamine. The resulting solution was stirred for 1 h, thenconcentrated in vacuo. The residue was taken up in chloroform, driedover Na₂SO₄, and concentrated in vacuo. Purification of the residue bysilica gel chromatography using 10% methanol in chloroform provided21.35 g (55%) of the desired compound. ¹H NMR (DMSO-d₆) δ 1.34 (d, J=7Hz, 6H), 2.56 (s, 3H), 3.30 (heptet, J=7 Hz, 1H), 4.16 (s, 2H), 7.63 (s,1H). Mass spectrum: (M+H)⁺=171.

R. N-(((4-Nitrophenyl)oxy)carbonyl)-L-valine Methyl Ester

A solution of 66.1 g (0.328 mol) of 4-nitrophenyl chloroformate in 1.2liters of CH₂Cl₂ was cooled to 0° C. and treated with L-valine methylester hydrochloride. The resulting mixture was treated slowly, withstirring, with 68.9 ml (0.626 mol) of 4-methylmorpholine. The resultingsolution was allowed to slowly warm to ambient temperature and wasstirred overnight. After washing with 3 portions of 10% aqueous NaHCO₃,the solution was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel chromatography by eluting withchloroform to provide the desired compound. ¹H NMR (DMSO-d₆) δ 0.94 (d,J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H), 2.12 (octet, J=7 Hz, 1H), 3.69 (s,3H), 4.01 (dd, J=8, 6 Hz, 1H), 7.41 (dt, J=9, 3 Hz, 2H), 8.27 (dt, J=9,3 Hz, 2H), 8.53 (d, J=8 Hz, 1H). Mass spectrum: (M+NH₄)⁺=314.

S.N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

A solution of 15.7 g (92 mmol) of2-isopropyl-4-(((N-methyl)amino)methyl)thiazole in 200 ml of THF wascombined with a solution of 20.5 g (69 mmol) ofN-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester. The resultingsolution was treated with 1.6 g of 4-dimethylaminopyridine and 12.9 ml(92 mmol) of triethylamine, heated at reflux for 2 h, allowed to cool,and concentrated in vacuo. The residue was taken up in CH₂Cl₂, washedextensively with 5% aqueous K₂CO₃, dried over Na₂SO₄, and concentratedin vacuo. The resulting product mixture was purified by silica gelchromatography using chloroform as an eluent to provide 16.3 g (54%) ofthe desired compound. ¹H NMR (DMSO-d₆) δ 0.88 (d, J=7 Hz, 3H), 0.92 (d,J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 2.05 (octet, J=7 Hz, 1H), 2.86 (s,3H), 3.25 (heptet, J=7 Hz, 1H), 3.61 (s, 3H), 3.96 (dd, J=8, 7 Hz, 1H),4.44 (AA′, 2H), 6.58 (d, J=8 Hz, 1H), 7.24 (s, 1H). Mass spectrum:(M+H)⁺=328.

T.N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

A solution of 1.42 g (4.3 mmol) of the resultant compound of Example 1Sin 17 ml of dioxane was treated with 17.3 ml of 0.50 M aqueous LiOH. Theresulting solution was stirred at ambient temperature for 30 min,treated with 8.7 ml of 1 M HCl, and concentrated in vacuo. The residuewas taken up in dichloromethane, washed with water, dried over Na₂SO₄,and concentrated in vacuo to provide 1.1 g (81%) of the desiredcompound. Mass spectrum: (M+H)⁺=314.

U.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 70 mg (0.223 mmol) ofN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine,79 mg (0.186 mmol) of(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane,30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266mmol) of N-ethyl-N′-dimethylaminopropyl carbodiimide in 2 ml of THF wasstirred at ambient temperature for 16 h. The resulting solution wasconcentrated in vacuo, and the residue was purified by silica gelchromatography using 97:3 CH₂Cl₂:CH₃OH to provide 100 mg (74%) of thedesired compound (R_(f) 0.4, 95:5 CH₂Cl₂:CH₃OH) as a solid.

¹H NMR (d₆-DMSO) δ 0.73 (d, J=7 Hz, 6H), 1.30 (d, J=7 Hz, 6H), 1.45 (m,2H), 1.87 (m, 1H), 2.5-2.7 (m, 4H), 2.87 (s, 3H), 3.23 (heptet, J=7 Hz,1H), 3.57 (m, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 4.15 (m, 1H), 4.44 (AA′,2H), 4.62 (d, J=6 Hz, 1H), 5.13 (AA′, 2H), 6.01 (d, J=9 Hz, 1H), 6.89(d, J=9 Hz, 1H), 7.1-7.2 (m, 11H), 7.68 (d, J=9 Hz, 1H), 7.85 (s, 1H),9.05 (s, 1H). Mass spectrum: (M+H)⁺=721. Anal. Calcd forC₃₇H₄₈N₆O₅S₂0.5H₂O: C, 60.88; H, 6.77; N, 11.51. Found: C, 60.68; H,6.53; N, 11.36.

EXAMPLE 2

Following the procedures of Example 1, the following compounds can beprepared:

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclohexyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,1-dimethyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclopentenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclohexenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclopentenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclohexenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,2-dimethyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclopentyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclohexyl)methyl-4-thiazolyl)methyl)amino)carbonyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-benzyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl-1-ethenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(4-fluoro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-chloro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-methoxy)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-methoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyloxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(N,N-dimethylamino)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-ethyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

EXAMPLE 3 A. N-(((4-Nitrophenyl)oxy)carbonyl)-L-alanine Methyl Ester

Using the procedure of Example 1R, but replacing L-valine methyl esterhydrochloride with L-alanine methyl ester hydrochloride provided thedesired compound (R_(f) 0.25, dichloromethane) in 95% yield.

B.N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-alanineMethyl Ester

Using the procedure of Example 1S, but replacingN-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester with theresultant compound of Example 3A provided, after silica gelchromatography using 97:3 CH₂Cl₂:CH₃OH, the desired compound (R_(f)0.55, 95:5 CH₂Cl₂:CH₃OH) in 24% yield. ¹H NMR (CDCl₃) δ 1.39 (d, J=7 Hz,6H), 1.43 (d, J=7 Hz, 3H), 2.98 (s, 3H), 3.28 (heptet, J=7 Hz, 1H), 3.74(s, 3H), 4.46 (s, 2H), 4.49 J=7 Hz, 1H), 6.12 (br, 1H), 6.98 (s, 1H).Mass spectrum: (M+H)⁺=300.

C.N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-alanine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 3B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 3C provided, after silica gelchromatography using 97:3 CH₂Cl₂:CH₃OH, 70 mg (35%) of the desiredcompound (R_(f) 0.36, 95:5 CH₂Cl₂:CH₃OH), mp. 56-58° C. Mass spectrum:(M+H)⁺=693. Anal. Calcd for C₃₅H₄₄N₆O₅S₂.0.5H₂O: C, 59.89; H, 6.46; N,11.97. Found: C, 60.07; H, 6.39; N, 12.00.

EXAMPLE 4 A. 2-Isopropyl-4-(((N-ethyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing 40% aqueous methylaminewith 70% aqueous ethylamine provided the crude desired compound. ¹H NMR(DMSO-d₆) δ 1.12 (t, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 6 H), 2.78 (q, J=7Hz, 2H), 3.27 (q, J=7 Hz, 1H), 3.97 (s, 2H), 7.44 (s, 1H).

B.N-((N-Ethyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isopropyl-4-(((N-ethyl)amino)methyl)-thiazole provided, after silicagel chromatography using 98:2 CHCl₃:CH₃OH, the desired compound (R_(f)0.5, 95:3 CH₂Cl₂:CH₃OH) in 54% yield. ¹H NMR (CDCl₃) δ 0.94 (d, J=7 Hz,3H), 0.98 (d, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3H), 1.39 (d, J=7 Hz, 6H),2.16 (m, 1H), 3.25-3.50 (m, 3H), 3.71 (s, 3H), 4.38 (dd, J=8, 6 Hz, 1H),4.46 (AA′, 2H), 6.13 (br, 1H), 7.00 (s, 1H). Mass spectrum: (M+H)⁺=342.

C.N-((N-Ethyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 4B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-Ethyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 4C provided, after silica gelchromatography using 98:2 CHCl₃:CH₃OH, 60 mg (35%) of the desiredcompound (R_(f) 0.4, 95;5 CH₂Cl₂:CH₃OH), mp. 58-60° C. Mass spectrum:(M+H)⁺=735.

EXAMPLE 5 A. Ethyl 2-Isopropylthiazole-4-carboxylate

A solution of 2.35 g (23 mmol) of 2-methylpropane-thioamide and 2.89 ml(23 mmol) of ethyl bromopyruvate in 75 ml of acetone was treated withexcess MgSO₄ and heated at reflux for 2.5 h. The resulting mixture wasallowed to cool, filtered, and concentrated in vacuo to an oil, whichwas taken up in chloroform, washed sequentially with aqueous NaHCO₃ andbrine, dried over Na₂SO₄, and concentrated. The residue was purified bychromatography on silica gel using chloroform as an eluent to provide3.96 g (86%) of the desired compound, R_(f) 0.21 (chloroform) as an oil.¹H NMR (CDCl₃) δ 1.41 (t, J=8 Hz, 3H), 1.42 (d, J=7 Hz, 6H), 3.43(heptet, J=7 Hz, 1H), 4.41 (q, J=8 Hz, 2H), 8.05 (s, 1H). Mass spectrum:(M+H)⁺=200.

B. 4-(Hydroxymethyl)-2-isopropylthiazole

A solution of 10 ml (10 mmol) of lithium aluminum hydride in toluene wasdiluted in a dry flask under N₂ atmosphere with 75 ml of THF. Theresulting mixture was cooled to 0° C. and treated dropwise with asolution of 3.96 g (20 mmol) of ethyl 2-isopropyl-4-thiazolecarboxylatein 10 ml of THF. After addition, the solution was stirred at 0° C. for 3h, diluted with ether, and treated with a small amount of aqueousRochelle's salt. After stirring, the slurry was filtered, washed withethyl acetate, and the combined filtrates were concentrated in vacuo.The residue was purified by silica gel chromatography using 2% methanolin chloroform to provide 2.18 g (69%) of the desired compound, R_(f)0.58 (4% methanol in chloroform). ¹H NMR (CDCl₃) δ 1.39 (d, J=7 Hz, 6H),2.94 (br, 1H), 3.31 (heptet, J=7 Hz, 1H), 4.74 (s, 2H), 7.04 (s, 1H).Mass spectrum: (M+H)⁺=158.

C. α-Isocyanato-valine Methyl Ester

A suspension of L-valine methyl ester hydrochloride (49 g, 0.29 mol) intoluene (700 ml) was heated to 100° C. and phosgene gas was bubbled intothe reaction mixture. After approximately 6 h, the mixture becamehomogeneous. The bubbling of phosgene was continued for 10 more min,then the solution was cooled with the bubbling of N₂ gas. The solventwas then evaporated and the residue chased with toluene two times.Evaporation of solvent gave 40.8 g (89%) of the crude desired compound.

D. N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valine Methyl Ester

A solution of 2.18 g (15 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole,15.8 mmol of α-isocyanato-valine methyl ester and 1.5 mmol of4-dimethylaminopyridine in 75 ml of dichloromethane was heated at refluxfor 5 h. The resulting solution was washed successively with 10% citricacid, aqueous NaHCO₃ and brine, dried over Na₂SO₄, and concentrated invacuo. Silica gel chromatography of the residue using 5% ethyl acetatein chloroform provided 2.67 g (57%) of the pure desired compound, R_(f)0.46 (4% methanol in chloroform). NMR ¹H NMR (DMSO-d₆) δ 1.26 (d, J=8Hz, 3H), 1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 3.63 (s, 3H),4.10 (pentet, J=8 Hz, 1H), 5.02 (s, 2H), 7.47 (s, 1H), 7.81 (d, J=8 Hz,1H). Mass spectrum: (M+H)⁺=287.

E. N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valine Using theprocedure of Example 1T, but replacing the resultant compound of Example1S with the resultant compound of Example 5D provided the desiredcompound. F.(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 5E provided, after silica gelchromatography using 2% methanol in chloroform, 110 mg (58%) of thedesired compound (R_(f) 0.44, 10% methanol in chloroform), mp. 142-145°C. Mass spectrum: (M+H)⁺=708.

EXAMPLE 6(2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 5E and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 105 mg (55%) of the desired compound (R_(f) 0.33, 10%methanol in chloroform), mp. 172-174° C. Mass spectrum: (M+H)⁺=708.

EXAMPLE 7 A. N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alanine MethylEster

A solution of 1.12 g (5.56 mmol) of 4-nitrophenyl chloroformate in 20 mlof CH₂Cl₂ was cooled to 0° C. and treated sequentially with 0.8 g (5.1mmol) of 4-(hydroxymethyl)-2-isopropylthiazole and 0.6 ml (5.6 mmol) of4-methylmorpholine. The resulting solution was stirred at 0° C. for 1 h,diluted with CH₂Cl₂, washed with three portions of aqueous NaHCO₃, driedover Na₂SO₄, and concentrated in vacuo to give crude2-isopropyl-4-(p-nitrophenyloxycarbonyloxymethyl)thiazole. A portion(0.53 g, 1.65 mmol) of the residue was taken up in 20 ml of chloroform,treated with 0.23 g (1.67 mmol) of L-alanine methyl ester hydrochlorideand 0.36 ml (3.3 mmol) of 4-methylmorpholine, and heated at reflux for16 h. After being allowed to cool, the solven was removed in vacuo, andthe residue was purified by silica gel chromatography using 2% methanolin chloroform to provide 0.45 g (94%) of the desired compound, R_(f)0.43 (5% methanol in CH₂Cl₂). ¹H NMR (DMSO-d₆) δ 1.26 (d, J=8 Hz, 3H),1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 3.63 (s, 3H), 4.10 (p,J=8 Hz, 1H), 5.02 (s, 2H), 7.47 (s, 1H), 7.81 (d, J=8 Hz, 1H). Massspectrum: (M+H)⁺=287.

B. N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alanine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 7A provided thedesired compound.

C.(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 7B provided, after silica gelchromatography using 1% methanol in chloroform, 110 mg (69%) of thedesired compound (R_(f) 0.4, 5% methanol in CH₂Cl₂), mp. 59-61° C. Massspectrum: (M+H)⁺=680. Anal. Calcd for C₃₄H₄₁N₅O₆S₂.0.5H₂O: C, 59.28; H,6.15; N, 10.17. Found: C, 59.37; H, 5.96; N, 10.18.

EXAMPLE 8 A.(5S,1′S)-5-(1-(tert-Butyloxycarbonylamino)-2-phenylethyl)-dihydrofuran-2(3H)-one

Prepared from commercially available ethyl-3-bromo-propionate by usingthe procedure of A. E. DeCamp, et al., (Tetrahedron Lett. 1991, 32,1867).

B.(5S1′S)-5-(1-(tert-Butyloxycarbonylamino)-2-phenylethyl)-3-carboethoxy-dihydrofuran-2(3H)-one

Lithium diisopropylamide (LDA) was prepared by dropwise addition of 16.5ml (41.2 mmol) of 2.5 M n-BuLi to a solution of 5.8 ml (41.2 mmol) ofdiisopropyl amine in 30 ml of dry tetrahydrofuran at −78° C. The LDAsolution was stirred for 30 min at −78° C. and 6.0 g (19.6 mmol) of theresultant compound of Example 8A in 30 ml of dry tetrahydrofuran wasadded dropwise. The reaction mixture was stirred for 30 min at −78° C.and 4.7 ml (49.1 mmol) of ethyl chloroformate was then added. Afterbeing stirred at −78° C. for 5 h, the reaction was quenched withsaturated aqueous NH₄Cl, extracted with three 60 ml portions ofdichloromethane. The combined organic layers were dried over Na₂SO₄,concentrated in vacuo and the residue was purified by silica gelchromatography using 25% ethyl acetate in hexane to provide 4.73 g (64%)of the desired compound as a white solid. Mass spectrum: (M+H)⁺=378.

C.(5S,1′S)-5-(1-(tert-Butyloxycarbonylamino)-2-phenylethyl)-3-carboethoxy-3-((5-thiazolyl)methyl)dihydrofuran-2(3H)-one

Sodium metal (536 mg, 23.3 mmol) was dissolved in 10 ml of absoluteethanol. A solution of 4.0 g (10.6 mmol) of the resultant compound ofExample 8B in 50 ml of absolute ethanol was added dropwise. The mixturewas stirred at ambient temperature for 20 min and 5-chloromethylthiazolehydrochloride was then added. After being stirred at ambient temperaturefor 60 h, the reaction was cooled in an ice bath, neutralized with 10%citric acid to pH ˜6 and extracted with four 50 ml portions ofdichloromethane. The combined organic layers were dried over Na₂SO₄,concentrated in vacuo and the residue was purified by silica gelchromatography using 10% methanol in dichloromethane to provide 3.88 g(78%) of the desired compound as a white foamy solid. Mass spectrum:(M+H)⁺=475.

D. (3S,5S,1′S)-5-(1-(tert-Butyloxycarbonylamino)-2-phenylethyl)-3-((5-thiazolyl)methyl)dihydrofuran-2(3H)-one

A solution of 3.88 g (8.18 mmol) of the resultant compound of Example 8Cin 65 ml of dimethoxyethane was treated with 32.7 ml (32.7 mmol) of 1 Maqueous lithium hydroxide. After being stirred at ambient temperaturefor 4 h, the bulk of the 1,2-dimethoxyethane was removed in vacuo. Theremaining mixture was treated with 10% citric acid to pH 4˜5 andextracted with four 50 ml portions of dichloromethane. The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo to givethe crude acid. The acid was dissolved in 50 ml of toluene, heated atreflux for 15 h. The solvent was removed in vacuo, and the residue wasseparated by silica gel chromatography using 50% ethyl acetate in hexaneto provide 0.86 g (26%) of 3R isomer and 1.58 g (48%) of the desiredcompound as a white solid. ¹H NMR (CDCl₃) δ 1.40 (s, 9H), 1.84 (m, 1H),2.21 (ddd, 1H), 2.82-2.99 (m, 3H), 3.07 (dd, 1H), 3.43 (dd, 1H), 3.97(br q, 1H), 4.36 (ddd, 1H), 4.55 (br d, 1H), 7.21-7.33 (m, 5H), 7.63 (s,1H), 8.69 (s, 1H). Mass spectrum: (M+H)⁺=403.

E.(2S,4S,5S)-4-(tert-Butyldimethylsilyfoxy)-5-(tert-butyloxycarbonylamino)-6-phenyl-2-((5-thiazolyl)methyl)hexanoicAcid

A solution of 1.50 g (3.73 mmol) of the resultant compound of Example 8Din 80 ml of a 2:1 mixture of 1,2-dimethoxyethane and water was treatedwith 14.9 ml (14.9 mmol) of 1 M aqueous lithium hydroxide. After beingstirred at ambient temperature for 1.5 h, the bulk of the1,2-dimethoxyethane was removed in vacuo. The remaining mixture wastreated with 10% citric acid to pH 4˜5 and extracted with four 50 mlportions of dichloromethane. The combined organic layers were dried overNa₂SO₄ and concentrated in vacuo to give 1.48 g of the crude hydroxyacid. This hydroxy acid was dissolved in 14 ml of dry DMF and 2.64 g(17.5 mmol) of tert-butyldimethylsilyl chloride and 2.23 g (32.8 mmol)of imidazole were added. After being stirred at ambient temperature for18 h, 28 ml of methanol was added to the mixture. Stirring was continuedfor 4 h and the solvents were then removed in vacuo. The residue wastreated with 10% citric acid to pH 4˜5 and extracted with four 50 mlportions of dichloromethane. The combined organic layers were dried overNa₂SO₄, concentrated in vacuo and the residue was purified by silica gelchromatography using 10% methanol in dichloromethane to provide 1.70 g(85%) of the desired compound as a white foamy solid. Mass spectrum:(M+H)⁺=529.

Anal. Calcd for C₂₇H₄₂N₂O₅SSi.0.5H₂O: C, 59.64; H, 7.97; N, 5.15; Found:C, 59.71; H, 7.83; N, 5.31.

F.(2S,3S,5S)-5-((((Benzyl)oxy)carbonyl)amino)-3-(tert-butyldimethylsilyloxy)-2-(tert-butyloxycarbonylamino)-1-phenyl-6-(5-thiazolyl)hexane

A solution of 500.0 mg (0.935 mmol) of the resultant compound of Example8E, 402 μl (1.87 mmol) of diphenyl-phosphoryl azide and 326 μl (2.38mmol) of triethylamine in 5 ml of dioxane was heated at 70° C. for 1 h.Benzyl alcohol (483 μl, 4.67 mmol) was subsequently added. The mixturewas stirred at 80° C. for 24 h. The solvents were removed in vacuo andthe residue was purified by silica gel chromatography using 10% methanolin dichloromethane to provide 598.1 mg (100%) of the desired compound asa white foamy solid. Mass spectrum: (M+H)⁺=640.

G.(2S,3S,5S)-5-((((Benzyl)oxy)carbonyl)amino)-2-(tert-butyloxycarbonylamino)-1-phenyl-6-(5-thiazolyl)-3-hydroxyhexane

A solution of 570.6 mg (0.892 mmol) of the resultant compound of Example8F in 25 ml of tetrahydrofuran was treated with 0.89 ml of 1 M solutionof tetrabutylammonium fluoride in tetrahydrofuran. After being stirredat ambient temperature for 20 h, the solvent was removed in vacuo andthe residue was purified by silica gel chromatography using 10% methanolin dichloromethane to provide 295.6 mg (63%) of the desired compound asa white solid. ¹H NMR (CDCl₃) δ 1.39 (s, 9H), 1.54 (m, 2H), 2.87 (m,2H), 3.08 (m, 2H), 3.69 (m, 2H), 3.96 (m, 1H), 4.77 (br d, 1H), 5.08 (s,2H), 5.11 (br s, 1H), 7.18-7.36 (m, 10H), 7.53 (s, 1H), 8.67 (s, 1H).Mass spectrum: (M+H)⁺=526.

H. (2S,3S,5S)-2,5-Diamino-1-phenyl-6-(5-thiazolyl)-3-hydroxyhexane

The resultant compound of Example 8G (201.2 mg, 0.383 mmol) wasdissolved in 1 ml of acetic acid saturated with hydrogen bromide andstirred at ambient temperature for 1 h. The solvent was removed invacuo. The residue was treated with 2 ml of saturated aqueous NaHCO₃,extracted with five 5 ml portions of dichloromethane. The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo toprovide 99.3 mg (89%) of the desired compound as a white solid. Massspectrum: (M+H)⁺=292.

I.(4S,6S,1′S)-6-(1-Amino-2-phenylethyl)-2-phenyl-4-((5-thiazolyl)methyl)-3-aza-2-bora-1-oxacyclohexane

A solution of 95.7 mg (0.328 mmol) of the resultant compound of Example8H and 40.0 mg (0.328 mmol) of phenylboric acid in 5 ml of toluene washeated at reflux and the water azeotropically removed with the aid of aDean Stark trap until the distillate was clear. The solvent was thenremoved in vacuo to provided 124.3 mg (100%) of the desired compound asa resin. Mass spectrum: (M+H)⁺=378.

J.(2S,3S,5S)-5-Amino-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane

A solution of 100.0 mg (0.265 mmol) of the resultant compound of Example8I and 74.0 mg (0.265 mmol) of((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 5 ml oftetrahydrofuran was stirred at ambient temperature for 24 h. The solventwas then removed in vacuo. The residue was dissolved in 20 ml ofdichloromethane, washed with three 5 ml portions of 0.5N NaOH and two 5ml portions of water. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography using 2% methanol and 2% isopropylamine in chloroform toprovide 22.8 mg (20%) of the desired compound as a white solid. Massspectrum: (M+H)⁺=433.

K.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinylamino)-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 8J provided 16.7 mg (47%) of thedesired compound as a white solid. ¹H NMR (CDCl₃) δ 0.90 (d, 3H), 0.94(d, 3H), 1.38 (d, 6H), 1.63 (m, 2H), 2.32 (m, 1H), 2.85 (m, 2H), 2.97(s, 3H), 3.04 (m, 2H), 3.31 (m, 1H), 3.68 (m, 1H), 3.77 (m, 1H), 3.96(m, 1H), 4.16 (m, 1H), 4.39 (s, 2H), 5.22 (m, 4H), 6.40 (br s, 1H), 6.80(br d, 1H), 7.04 (s, 1H), 7.18-7.28 (m, 5H), 7.55 (s, 1H), 7.83 (s, 1H),8.58 (s, 1H), 8.80 (s, 1H). Mass spectrum: (M+H)⁺=728.

EXAMPLE 9 A. 4-(Chloromethyl)-2-(dimethylamino)thiazole

A mixture of 15 g (144 mmol) of N,N-dimethylthiourea and excess MgSO₄ in350 ml of acetone was heated to reflux and treated dropwise with asolution of 18.3 g (144 mmol) of 1,3-dichloroacetone in 35 ml ofacetone. The resulting mixture was heated at reflux for 1.5 h, allowedto cool, filtered, and concentrated in vacuo. The residue was purifiedby silica gel chromatography using 20% ethyl acetate in hexane toprovide 14.0 g (70%) of the desired compound.

B. 2-(N,N-Dimethylamino)-4-(hydroxymethyl)thiazole

A solution of 5.186 g (29 mmol) of4-(chloromethyl)-2-(dimethylamino)thiazole in 100 ml of 1:1 THF/H₂O wascooled to 0° C. and treated dropwise with a solution of 5.73 g (29 mmol)of silver tetrafluoroborate in 50 ml of 1:1 THF/H₂O. After being stirredfor 1 h, the mixture was filtered, the solid mass was washed with ethylacetate, and the combined filtrates were concentrated in vacuo. Theblack residue was purified by silica gel chromatography to provide 0.80g (17%) of the desired compound (R_(f) 0.24, 6% methanol in chloroform)as an oil. ¹H NMR (CDCl₃) δ 2.67 (br, 1H), 3.09 (s, 6H), 4.54 (s, 2H),6.35 (s, 1H). Mass spectrum: (M+H)⁺=159.

C. N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valine MethylEster

A solution of 505 mg (3.19 mmol) of2-(N,N-dimethylamino)-4-(hydroxymethyl)thiazole, 3.19 mmol ofα-isocyanato-L-valine methyl ester, and 100 mg of4-dimethylaminopyridine in 30 ml of dichloromethane was heated at refluxfor 3 h. The resulting solution was allowed to cool, diluted withdichloromethane, washed sequentially with 10% citric acid, aqueousNa₂CO₃, and brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel chromatography using 2% methanol inchloroform to provide 0.95 g (95%) of the desired compound, R_(f) 0.42(4% methanol in chloroform). ¹H NMR (CDCl₃) δ 0.84 (d, J=7 Hz, 3H), 0.93(d, J=7 Hz, 3H), 2.12 (m, 1H), 3.11 (s, 6H), 3.73 (s, 3H), 4.24 (dd,J=8, 4 Hz, 1H), 4.99 (s, 2H), 5.26 (br d, 1H), 6.49 (s, 1H). Massspectrum: (M+H)⁺=316.

D. N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 9C provided thedesired compound. Mass spectrum: (M+H)⁺=302.

E.(2S,3S,5S)-5-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 9D provided, after silica gelchromatography using 2% methanol in chloroform, 100 mg of the desiredcompound (R_(f) 0.49, 10% methanol in chloroform), mp. 162-165° C. Massspectrum: (M+H)⁺=709.

EXAMPLE 10(2S,3S,5S)-2-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 9D and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 25 mg (10%) of the desired compound (R_(f) 0.49, 10%methanol in chloroform), mp. 157-159° C. Mass spectrum: (M+H)⁺=709.

EXAMPLE 11 A. 4-((Amino)thiocarbonyl)morpholine

A solution of 3.35 g (18.8 mmol) of thiocarbonyl diimidazole in 100 mlof THF was treated with 0.82 ml (9.4 mmol) of morpholine. After beingstirred at ambient temperature for 3.5 h, an additional 0.82 ml portionof morpholine was added, and stirring was continued. After 6 h, thesolution was treated with excess concentrated aqueous ammonia, andstirred overnight. The resulting solution was concentrated in vacuo,taken up in chloroform, separated from the aqueous phase, dried overNa₂SO₄, and concentrated. Purification of the residue by silica gelchromatography using ethyl acetate provided 1.85 g (76%) of the desiredcompound, R_(f) 0.17 (10% methanol in chloroform), as a white solid. ¹HNMR (CDCl₃) δ 3.76 (m, 4H), 3.83 (m, 4H), 5.75 (br, 2H). Mass spectrum:(M+H)⁺=147.

B. Ethyl 2-(4-Morpholinyl)thiazole-4-carboxylate

A mixture of 1.85 g (12.7 mmol) of 4-((amino)thiocarbonyl)morpholine,1.59 ml (12.7 mmol) of ethyl bromopyruvate, and excess MgSO₄ in 50 ml ofacetone was heated at reflux for 2 h. The resulting mixture was allowedto cool, filtered, and concentrated in vacuo. The residue was taken upin chloroform, washed with aqueous NaHCO₃, dried over Na₂SO₄, andconcentrated. Silica gel chromatography using 1% methanol in chloroformprovided 1.7 g (55%) of the desired compound, R_(f) 0.70 (ethylacetate). Mass spectrum: (M+H)⁺=243.

C. 2-(4-Morpholinyl)-4-(hydroxymethyl)thiazole

A solution of 7.0 ml (7.0 mmol) of lithium aluminum hydride in toluenewas diluted with 10 ml of THF, cooled to 0° C., and treated with asolution of 1.7 g (7.0 mmol) of ethyl2-(4-morpholinyl)thiazole-4-carboxylate in 25 ml of THF. The resultingsolution was stirred for 1 h, quenched cautiously with aqueousRochelle's salts, diluted with chloroform, filtered, dired over Na₂SO₄,and concentrated in vacuo. Silica gel chromatography using 2-4% methanolin chloroform provided 856 mg (61%) of the desired compound, R_(f) 0.16(4% methanol in chloroform). ¹H NMR (CDCl₃) δ 2.44 (br, 1H), 3.46 (t,J=5 Hz, 4H), 3.81 (t, J=5 Hz, 1H), 4.55 (br s, 2H), 6.45 (s, 1H). Massspectrum: (M+H)⁺=200.

D. N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valine Methyl Ester

Using the procedure of Example 9C but replacing2-(N,N-dimethylamino)-4-(hydroxymethyl)thiazole with2-(4-morpholinyl)-4-(hydroxymethyl)thiazole provided, after silica gelchromatography using 1% methanol in chloroform, the desired compound,R_(f) 0.54 (4% methanol in chloroform), in 65% yield. ¹H NMR (CDCl₃) δ0.97 (d, J=7 Hz, 3H), 1.00 (d, J=7 Hz, 3H), 2.25 (m, 1H), 3.50 (dd, J=5,4 Hz, 2H), 3.76 (s, 3H), 3.84 (dd, J=5, 4 Hz, 2H), 4.67 (dd, J=9, 5 Hz,1H), 7.63 (br d, 1H), 8.02 (s, 1H).

E. N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 11D provided thedesired compound.

F.(2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 11E provided, after silica gelchromatography using 2% methanol in chloroform, 201 mg (92%) of thedesired compound (R_(f) 0.19, 4% methanol in chloroform), mp. 1.69-170°C. Mass spectrum: (M+H)⁺=751.

EXAMPLE 12(2S,3S,5S)-2-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 11E and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 196 mg (90%) of the desired compound (R_(f) 0.19, 4%methanol in chloroform), mp. 146-148° C. Mass spectrum: (M+H)⁺=751.

EXAMPLE 13 A. 1-((Amino)thiocarbonyl)pyrrolidine

Using the procedure of Example 11A but replacing morpholine withpyrrolidine, and stirring the solution for six days after addition ofaqueous ammonia provided the desired compound. ¹H NMR (CDCl₃) δ 1.97 (m,2H), 2.11 (m, 2H), 3.38 (br t, 2H), 3.85 (br t, 2H), 5.56 (br, 2H). Massspectrum: (M+H)⁺=131.

B. Ethyl 2-(1-Pyrrolidinyl)thiazole-4-carboxylate

Using the procedure of Example 11B but replacing4-((amino)thiocarbonyl)morpholine with1-((amino)thiocarbonyl)pyrrolidine provided the desired compound. ¹H NMR(CDCl₃) δ 1.37 (t, J=7 Hz, 3H), 2.04 (m, 4H), 3.51 (m, 4H), 4.35 (q, J=7Hz, 2H), 7.37 (s, 1H). Mass spectrum: (M+H)⁺=227.

C. 2-(1-Pyrrolidinyl)-4-(hydroxymethyl)thiazole

Using the procedure of Example 11C but replacing ethyl2-(4-morpholinyl)thiazole-4-carboxylate with ethyl2-(1-pyrrolidinyl)thiazole-4-carboxylate provided, after silica gelchromatography using 2-4% methanol in chloroform, the desired compound(R_(f) 0.26, 4% methanol in chloroform) in 53% yield. ¹H NMR (CDCl₃) δ2.04 (m, 4H), 2.75 (br, 1H), 3.45 (m, 4H), 4.56 (s, 2H), 6.32 (s, 1H).Mass spectrum: (M+H)⁺185.

D. N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valine MethylEster

Using the procedure of Example 9C but replacing2-(N,N-dimethylamino)-4-(hydroxymethyl)thiazole with2-(1-pyrrolidinyl)-4-(hydroxymethyl)thiazole provided, after silica gelchromatography using 1.5% methanol in chloroform, the desired compound(R_(f) 0.34). ¹H NMR (CDCl₃) δ 0.89 (d, J=7 Hz, 6H), 2.04 (m, 4H), 2.14(m, 1H), 3.46 (m, 4H), 3.74 (s, 3H), 4.30 (dd, J=9, 4 Hz, 1H), 5.01 (s,2H), 5.33 (br d, 1H), 6.44 (s, 1H). Mass spectrum: (M+H)⁺=342.

E. N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 13D provided thedesired compound.

F.(2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 13E provided, after silica gelchromatography using 1-3% methanol in chloroform, 120 mg (53%) of thedesired compound, mp. 146-148° C. Mass spectrum: (M+H)⁺=735.

EXAMPLE 14(2S,3S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinylamino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 13E and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 89 mg (39%) of the desired compound (R_(f) 0.16, 4% methanolin chloroform), mp. 165-167° C. Mass spectrum: (M+H)⁺=735.

EXAMPLE 15 A. 2-Isopropyl-4-(((N-cyclopropyl)amino)methyl)thiazole

A solution of 1.8 g (10.2 mmol) of 4-(chloromethyl)-2-isopropylthiazolehydrochloride in 10 ml of chloroform was added dropwise with stirring to10 ml of cyclopropylamine. The resulting solution was stirred at ambienttemperature for 16 h, concentrated in vacuo and purified by silica gelchromatography using 5% methanol in chloroform to provide 0.39 g (19%)of the desired compound. ¹H NMR (DMSO-d₆) δ 0.24 (m, 2H), 0.35 (m, 2H),1.30 (d, J=7 Hz, 6H), 2.10 (tt, J=12, 3 Hz, 1H), 3.23 (heptet, J=7 Hz,1H), 3.77 (s, 2H), 7.21 (s, 1H). Mass spectrum: (M+H)⁺=197.

B.N-((N-Cyclopropyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-alanineMethyl Ester

Using the procedure of Example 1S, but replacingN-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester withN-(((4-nitrophenyl)oxy)carbonyl)-L-alanine methyl ester and replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with the resultantcompound of Example 15A provided, after silica gel chromatography using1% methanol in chloroform, the desired compound (R_(f) 0.54, 5% methanolin chloroform) in 56% yield. ¹H NMR (DMSO-d₆) δ 0.70 (m, 2H), 0.80 (m,2H), 1.30 (d, J=7 Hz, 6H), 1.34 (d, J=7 Hz, 3H), 2.57 (m, 1H), 3.22(heptet, J=7 Hz, 1H), 3.62 (s, 3H), 4.23 (pentet, J=7 Hz, 1H), 4.44(AA′, 2H), 6.54 (d, J=7 Hz, 1H), 7.05 (s, 1H). Mass spectrum:(M+H)⁺=326.

C.N-((N-Cyclopropyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl-L-alanine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 15B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-Cyclopropyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 15C provided, after silica gelchromatography using 1% methanol in chloroform, 74 mg (40%) of thedesired compound (R_(f) 0.25, 5% methanol in chloroform), mp. 65-67° C.Mass spectrum: (M+H)⁺=719. Anal. Calcd for C₃₇H₄₆N₆O₅S₂.0.5H₂O: C,61.05; H, 6.51; N, 11.54. Found: C, 61.08; H, 6.32; N, 11.44.

EXAMPLE 16 A. 2-Isopropylthiazole-4-carboxaldehyde

A solution of ethyl 2-isopropylthiazole-4-carboxylate (1 mmol) in 50 mlof dry dichloromethane was cooled to −78° C. under N₂ atmosphere andtreated dropwise with 1.2 mmol of diisobutylaluminum hydride (1.5 M intoluene). The resulting solution was stirred for 0.5 h, quenched withaqueous Rochelle salts, extracted with dichloromethane, dried overNa₂SO₄, and concentrated in vacuo to provide the crude desired compound.

B. 4-(1-Hydroxyethyl)-2-isopropylthiazole

A solution of the resultant compound of Example 16A (0.5 mmol) in 25 mlof dry THF was cooled to −20° C. under Ar atmosphere, treated with 0.5mmol of methylmagnesium chloride (3.0 M in THF), stirred for 15 min, andquenched with water. The mixture was extracted with ethyl acetate, driedover Na₂SO₄, and concentrated in vacuo to provide the crude desiredcompound.

C. N-(1-(2-Isopropyl-4-thiazolyl)ethoxycarbonyl)valine Methyl Ester

Using the procedure of Example 5D but replacing4-(hydroxymethyl)-2-isopropylthiazole with4-(1-hydroxyethyl)-2-isopropylthiazole provided the desired compound.

D. N-(1-(2-Isopropyl-4-thiazolyl)ethoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 16C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-(1-(2-Isopropyl-4-thiazolyl)ethoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 16D provided the desiredcompound.

EXAMPLE 17 A.N-((N-Cyclopropyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with the resultantcompound of Example 15A provided, after silica gel chromatography using1% methanol in chloroform, the desired compound (R_(f) 0.64, 5% methanolin chloroform) in 91% yield.

¹H NMR (DMSO-d₆) δ 0.73 (m, 2H), 0.82 (m, 2H), 0.90 (d, J=7 Hz, 6H),1.30 (d, J=7 Hz, 6H), 2.10 (octet, J=7 Hz, 1H), 2.62 (m, 1H), 3.23(heptet, J=7 Hz, 1H), 3.64 (s, 3H), 4.10 (dd, J=9, 6 Hz, 1H), 4.45 (AA′,2H), 6.29 (d, J=9 Hz, 1H), 7.06 (s, 1H). Mass spectrum: (M+H)⁺=354.

B.N-((N-Cyclopropyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 17A provided thedesired compound.

C.(2S,3S,5S)-5-(N-(N-((N-Cyclopropyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 17B provided, after silica gelchromatography using 1% methanol in chloroform, 85 mg (48%) of thedesired compound (R_(f) 0.30, 5% methanol in chloroform), mp. 65-66° C.Mass spectrum: (M+H)⁺=747. Anal. Calcd for C₃₉H₅₀N₆O₅S₂: C, 62.71; H,6.75; N, 11.25. Found: C, 62.74; H, 6.61; N, 11.03.

EXAMPLE 18 A. 4-Chloromethyl-4-hydroxy-2-isopropyloxazoline

To a solution of isobutyramide (9.876 g, 0.1122 mol) in acetone (130 mL)was added 1,3-dichloroacetone (10.0 g, 0.0748 mol), NaHCO₃ (9.429 g,0.1122 mol), and MgSO₄ (18.01 g, 0.1496 mol). The mixture was heated atreflux under argon for 63 hrs, then cooled to room temperature, vacuumfiltered, and concentrated in vacuo to a dark brown semi-solid. Theresidue was purified by SiO₂ flash chromatography using a gradient ofEtOAc/CH₂Cl₂ (5%, 10%, 20%, 40%) to obtain the desired product as anorange liquid (6.06 g, 0.0341 mol, 46%): ¹H NMR (CDCl₃) δ 1.20-1.28 (m,6H), 2.56-2.72 (m, 1H), 3.70 (s, 2H), 4.18 (d, J=9.6 Hz, 1H), 4.38 (d,J=9.6 Hz, 1H). Mass spectrum: (M+H)⁺=178, 180.

B. 4-Chloromethyl-2-isopropyloxazole

A solution of 4-chloromethyl-4-hydorxy-2-isopropyloxazoline (4.88 g,0.0275 mol) in 1,2-dichloroethane (20 mL) was added to a solution ofSOCl₂ (2.40 mL, 0.0329 mol) in 1,2-dichloroethane (80 mL) at 0° C. underargon, and the solution was heated to 70° C. After 15 min at 70° C., thereaction was cooled to room temperature and the solvent removed byrotary evaporation in vacuo. Drying the residue on high vacuum gave thedesired compound as a brown semi-solid (4.20 g, 0.0263 mol, 96%): ¹H NMR(CDCl₃) δ 1.36 (d, J=7.5 Hz, 6H), 3.03-3.18 (m, 1H), 4.50 (s, 2H), 7.56(s, 1H). Mass spectrum: (M+H)⁺=160, 162.

C. 2-Isopropyl-4-(((N-methyl)amino)methyl)oxazole

To 40% aqueous methylamine (100 mL) was added dropwise a suspension of4-chloromethyl-2-isopropyloxazole (4.20 g, 0.0263 mol) in p-dioxane/H₂O(1:1 (v/v), 20 mL) over a 25 min period. After stirring for 45 min atambient temperature, the volume was reduced to ca. 50 mL by rotaryevaporation in vacuo, and NaCl was added. The aqueous was extracted withCHCl₃ (4×100 mL), and the combined extract was dried over Na₂SO₄ andconcentrated in vacuo. The resulting brown liquid was chromatographed ona 200 g SiO₂ flash column with 2% iPrNH₂/CH₂Cl₂ followed by a gradientof iPrNH₂/MeOH/CH₂Cl₂ (0.5:2:97.5, 0.5:4:95.5). Concentration in vacuoof the product-containing fractions afforded the desired compound as agolden oil (2.89 g, 0.0187 mol, 71%): ¹H NMR (CDCl₃) δ 1.33 (d, J=6.9Hz, 6H), 2.46 (s, 3H), 2.99-3.14 (m, 1H), 3.64 (s, 2H), 42 (s, 1H). Massspectrum: (M+H)⁺=155, (M+NH₄)⁺=172.

D.N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

A solution of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester(0.903 g, 0.00305 mol) in anhydrous DMF (6 mL) was added to a solutionof 2-isopropyl-4-(((N-methyl)amino)methyl)oxazole (9, 0.470 g, 0.00305mol) in anhydrous DMF (6 mL) under argon, and the yellow solution wasstirred at room temperature for 30 min. Solvent was removed by rotaryevaporation in vacuo and the resulting oil dried on high vacuum for 1hr. The residue was applied to a 150 g SiO₂ flash column and eluted with20% EtOAc/CH₂Cl₂ and 3% MeOH/CH₂Cl₂. The material obtained afterconcentration of the product fractions was repurified on a 100 g SiO₂flash column with a gradient of MeOH/CH₂Cl₂ (1%, 2%, 3%) to obtain thedesired compound as an oil (0.515 g, 0.00165 mol, 54%): ¹H NMR (CDCl₃) δ0.97 (dd, J₁=9 Hz, J₂=6.9 Hz, 6H), 1.33 (d, J=6.9 Hz, 6H), 2.11-2.23 (m,1H), 2.98 (s, 3H), 3.00-3.13 (m, 1H), 3.77 (s, 3H), 4.23-4.36 (m, 2H),4.36-4.42 (m, 1H), 5.79-5.86 (br, d, 1H), 7.46 (s, 1H). Mass spectrum:(M+H)⁺=312.

E.N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine

To a solution of the resultant compound of Example 18D 10 (0.511 g,0.00164 mol) in p-dioxane (10 mL) and H₂O (5 mL) was added LiOHmonohydrate (0.103 g, 0.00246 mol). After stirring at room temperaturefor 1 hr, the p-dioxane was removed by rotary evaporation in vacuo, andthe remaining aqueous solution was treated with 1N aq HCl (2.46 mL) andextracted with ethyl acetate (4×100 mL). The combined organic extractwas washed with saturated brine and dried for 15 mins over Na₂SO₄.Concentration in vacuo followed by CH₂Cl₂ chases (2×) afforded thedesired compound as a white solid (0.480 g, 0.00161 mol, 98%): ¹H NMR(DMSO-d₆) δ 0.90 (dd, J₁=6.9 Hz, J₂=2.4 Hz, 6H), 1.24 (d, J=6.9 Hz, 6H),1.99-2.12 (m, 1H), 2.83 (s, 3H), 2.96-3.10 (m, 1H), 3.96 (dd, J₁=8.4 Hz,J₂=6 Hz, 1H), 4.19-4.32 (m, 2H), 6.26 (d, J=8.4 Hz, 1H), 7.80 (s, 1H).Mass spectrum: (M+H)⁺=298.

F.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valineprovided, after silica gel chromatography using 3-5-7% methanol inchloroform, 70 mg, (53%) of the desired compound. ¹H NMR (DMSO-d₆) δ0.74 (d, J=6.3 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.38-1.51 (m, 2H),1.80-1.94 (m, 1H), 2.54-2.74 (m, 5H), 2.83 (s, 3H), 2.94-3.09 (m, 1H),3.53-3.63 (m,1H), 3.76-3.97 (m, 2H), 4.08-4.35 (m, 3H), 4.63 (d, J=6 Hz,1H), 5.08-5.19 (m, 2H), 5.90 (d, J=8.7 Hz, 1H), 6.89 (d, J=9 Hz, 1H),7.07-7.25 (m, 12H), 7.68 (d, J=8.7 Hz, 1H), 7.77 (s, 1H), 7.86 (s, 1H),9.05 (s, 1H). High resolution mass spectrum: calcd for C₃₇H₄₉N₆O₆S:705.3434. Found: 705.3431 (M+H)⁺. Anal. Calcd for C₃₇H₄₈N₆O₆S.0.5H₂O: C,62.25; H, 6.92; N, 11.77. Found: C, 62.35; H, 6.86; N, 11.34.

EXAMPLE 19 A. Methyl Isocyanide

A 100 mL 3-neck flask (equipped with septum, stopper, and a short pathmini distillation head with cow collector cooled to −78° C.) was chargedwith p-toluenesulfonyl chloride (36.25 g, 0.1901 mol) and quinoline (60mL). The vigorously stirred solution was heated to 75° C. with thesystem under vacuum (H₂O aspirator with trap cooled to −40° C.). NeatN-methylformamide (7.50 g, 0.127 mol) was added via syringe in smallportions over 15 mins. The increasingly viscous solution was heated for10 mins, at which time gas evolution had ceased. Material in the cowcollector and in the vacuum trap were combined and vacuum distilled toprovide the compound as a colorless liquid (2.06 g, 0.0502 mol, 39%).

B. 5-((Diethoxy)methyl)oxazole

Prepared according to the procedure of Schöllkopf (J. Am. Chem. Soc. 112(10) 4070 (1990)). To a solution of methyl isocyanide (2.88 g, 0.0702mol) in THF (50 mL) under argon at −78° C. was added dropwisen-butyllithium solution (1.6M in hexanes, 44 mL) over 15 mins. Afterstirring for an additional 20 mins at −78° C., a solution of ethyldiethoxyacetate (12.62 g, 0.0702 mol) in THF (15 mL) was added dropwiseover 20 mins. The bath was allowed to warm to −30° C. over the next 2hrs and the reaction was then stirred at 0° C. for 30 mins. The reactionwas quenched at 0° C. with glacial HOAc (4.22 g, 0.0702 mol) and thesolvent was removed by rotary evaporation in vacuo. The golden solid waspartitioned with H₂O (45 mL) and EtOAc (200 mL), and the aqueousextracted with EtOAc (2×200 mL). The combined organic was washed withsatd aq NaCl, dried over Na₂SO₄, and concentrated in vacuo to a brownoil. Chromatography on a 300 g SiO₂ flash column with a gradient ofEtOAc/hexane (10%, 15%, 20%) afforded the desired compound as acolorless liquid (7.46 g, 0.0436 mol, 62%): ¹H NMR (CDCl₃) δ 1.25 (t,J=6.9 Hz, 6H), 3.56-3.70 (m, 4H), 5.62 (s, 1H), 7.26 (s, 1H), 7.86 (s,1H). Mass spectrum: (M+H)⁺=172.

C. 5-Oxazolecarboxaldehyde

A flask was charged with 5-((diethoxy)methyl)oxazole (1.02 g, 0.00596mol) and cooled to 0° C. A solution of trifluoroacetic acid/CH₂Cl₂ (1:1(v/v), 6.7 mL) and H₂O (0.39 mL) was added and the solution stirred at0° C. for 10 min. The solvent was removed in vacuo, and the residue wastreated with toluene and concentrated. Chromatography on a 100 g SiO₂flash column with a gradient of EtOAc/hexane (20%, 30%, 40%) affordedthe desired compound as a colorless liquid (0.344 g, 0.00354 mol, 59%):¹H NMR (CDCl₃) δ 7.89 (s, 1H), 8.12 (s, 1H), 9.87 (s, 1H). Massspectrum: (M+H)⁺=98.

D. 5-(Hydroxymethyl)oxazole

A solution of 5-oxazolecarboxaldehyde (0.627 g, 0.00646 mol) in MeOH (10mL) under argon at 0° C. was treated with NaBH₄ (0.247 g, 0.00646 mol).After 5 mins the reaction was quenched with acetone and the solventremoved by rotary evaporation in vacuo. Chromatography on a 100 g SiO₂flash column with a gradient of MeOH/CH₂Cl₂ (5%, 10%) afforded thedesired compound as a colorless oil (0.408 g, 0.00412 mol, 64%): ¹H NMR(CDCl₃) δ 2.03 (t, J=6.0 Hz, 1H), 4.70 (d, J=6.0 Hz, 2H), 7.04 (s, 1H),7.87 (s, 1H). MS (Cl/NH₃) m/e 117 (m+NH₄), 100 (m+H).

E. ((5-Oxazolyl)methyl)-(4-nitrophenyl)carbonate

A solution of 5-(hydroxymethyl)oxazole (1.31 g, 0.0132 mol) in CH₂Cl₂(70 mL) under argon at 0° C. was treated with triethylamine (1.90 mL,0.0139 mol) and 4-nitrophenyl chloroformate (2.75 g, 0.0132 mol). Afterstirring at 0° C. for 2.5 hrs, solvent was removed by rotary evaporationin vacuo and the yellow solid was dried on vacuum pump to provide thecrude desired compound.

F.(2S,3S,5S)-2-Amino-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of crude ((5-oxazolyl)methyl)-(4-nitrophenyl)carbonate (madefrom 0.0132 mol 5-(hydroxymethyl)oxazole) in THF (110 mL) under argonwas treated with a solution of(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane (3.76 g, 0.0132 mol)in THF (20 mL), and the reaction stirred at room temperature for 16 hrs.Solvent was removed by rotary evaporation in vacuo and the yellow foamdried on a vacuum pump. Chromatography on a 200 g SiO₂ flash column with5% MeOH/CH₂Cl₂, 2% iPrNH₂/CH₂Cl₂, and a gradient of iPrNH₂/MeOH/CH₂Cl₂(2:2:96, 2:5:93) afforded a mixture (1.74 g) of the desired compound and(2S,3S,5S)-5-amino-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.The mixture was applied to a 150 g SiO₂ flash column (deactivated with2% iPrNH₂/CH₂Cl₂) and eluted with 2% iPrNH₂/CH₂Cl₂ to afford the desiredcompound as a gummy light yellow solid (0.382 g, 0.933 mmol, 7%): ¹H NMR(DMSO-d₆) δ 1.16-1.30 (m, 1H), 1.36-1.47 (m, 1H), 2.56-2.66 (m, 2H),2.75-2.85 (m, 1H), 2.89-3.01 (m, 1H), 3.53-3.71 (m, 3H), 4.97 (d, J=2.4Hz, 2H), 7.01 (d, J=9 Hz, 1H), 7.11-7.32 (m, 14H), 8.36 (s, 1H). Massspectrum: (M+H)⁺=410.

G.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valineprovided, after silica gel chromatography using a gradient of 1%-4%methanol in dichloromethane, 145 mg (80%) of the desired compound. ¹HNMR (CDCl₃) δ 0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.39-1.50(m, 2H), 1.80-1.94 (m, 1H), 2.56-2.74 (m, 4H), 2.83 (s, 3H), 2.94-3.09(m, 1H), 3.52-3.62 (m, 1H), 3.72-3.84 (m, 1H), 3.88-3.92 (m, 1H),4.08-4.35 (m, 3H), 4.62 (d, J=6 Hz, 1H), 4.94 (s, 2H), 5.91 (d, J=8.4Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.06-7.26 (m, 11H), 7.69 (d, J=9 Hz, 1H),7.77 (s, 1H), 8.35 (s, 1H). Mass spectrum: (M+NH₄)⁺=706; (M+H)⁺=689.Anal. Calcd for C₃₇H₄₈N₆O₇.0.5H₂O: C, 63.68; H, 7.08; N, 12.04. Found:C, 63.50; H, 7.13; N, 11.60.

EXAMPLE 20(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 1% methanol inchloroform; 88 mg (55%) of the desired compound (R_(f) 0.4, 5% methanolin chloroform), mp. 59-61° C. Mass spectrum: (M+H)⁺=705. Anal. Calcd forC₃₇H₄₈N₆O₆S.0.5H₂O: C, 62.25; H, 6.92; N, 11.77. Found: C, 62.23; H,6.55; N, 11.57.

EXAMPLE 21 A. Methyl 4-isopropylthiazole-2-carboxylate

A mixture of 2.11 g (12.8 mmol) of 1-bromo-3-methylbutan-2-one (Gaudryand Marquet, Tetrahedron, 26, 5661 (1970)), 1.0 g (12.8 mmol) of ethylthiooxamate, and 1.70 g (14 mmol) of MgSO₄ in 50 ml of acetone washeated at reflux for 3 h. After being allowed to cool, the mixture wasfiltered, concentrated in vacuo, and purified by silica gelchromatography using chloroform to provide 0.29 g (11%) of the desiredcompound (R_(f) 0.9, 4% methanol in chloroform). ¹H NMR (DMSO-d₆) δ 1.27(d, J=7 Hz, 6H), 1.32 (t, J=7 Hz, 3H), 3.12 (heptet, J=7 Hz, 1H), 4.37(q, J=7 Hz, 2H), 7.73 (s, 1H). Mass spectrum: (M+H)⁺=200.

B. 2-(Hydroxymethyl-4-isopropylthiazole

Using the procedure of Example 5B, but replacing ethyl2-isopropyl-4-thiazolecarboxylate with methyl4-isopropylthiazole-2-carboxylate provided, after silica gelchromatography using 2% methanol in chloroform, the desired compound(R_(f) 0.3, 5% methanol in chloroform) in 96% yield.

C. N-((4-Isopropyl-2-thiazolyl)methoxycarbonyl)valine Methyl Ester

A solution of 1.4 mmol of α-isocyanato-valine methyl ester and 0.22 g(1.4 mmol) of 2-(hydroxymethyl)-4-isopropylthiazole in 10 ml ofchloroform was heated at reflux for 3 h. After being allowed to cool,the solvent was removed in vacuo, and the residue was purified by silicagel chromatography using 2% methanol in chloroform to provide 0.23 g(52%) of the desired compound (R_(f) 0.54, 5% methanol indichloromethane). NMR ¹H NMR (DMSO-d₆) δ 0.87 (d, J=7 Hz, 3H), 0.88 (d,J=7 Hz, 3H), 1.23 (d, J=7 Hz, 6H), 2.04 (octet, J=7 Hz, 1H), 3.01(heptet, J=7 Hz, 1H), 3.73 (s, 3H), 3.94 (dd, J=8, 6 Hz, 1H), 5.26 (AA′,2H), 7.28 (s, 1H), 7.92 (d, J=8 Hz, 1H). Mass spectrum: (M+H)⁺=315.

D. N-((4-Isopropyl-2-thiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 21C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-((4-Isopropyl-2-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 21D provided, after silica gelchromatography using 1% methanol in chloroform, 123 mg (61%) of thedesired compound (R_(f) 0.4, 5% methanol in chloroform), mp. 62-64° C.Mass spectrum: (M+H)⁺=708.

EXAMPLE 22 A. N,N-Diethylthiourea

A mixture of 6.24 g (35 mmol) of thiocarbonyl diimidazole and 3.6 ml (35mmol) of diethylamine in 50 ml of THF was stirred at ambient temperaturefor 5 h. The resulting solution was treated with 20 ml of 2 M aqueousNH₃ and stirred for 24 h. After removal of the solvent the residue waspurified by chromatography on silica gel to provide N,N-diethylthiourea(R_(f) 0.28, 4% methanol in chloroform).

B. Ethyl 2-(N,N-Diethylamino)thiazole-4-carboxylate

A solution of 0.972 g (7.36 mmol) of N,N-diethylthiourea and 1.02 ml(8.1 mmol) of ethyl bromopyruvate in 25 ml of acetone was treated withexcess solid MgSO₄ and heated at reflux for 1 h. The resulting mixturewas filtered, and concentrated in vacuo. Silica gel chromatography usingCHCl₃ provided 2.36 g (38%) of the desired compound as an oil. Massspectrum: (M+H)⁺=229.

C. 2-(N,N-Diethylamino)-4-(hydroxymethyl)thiazole

A solution of 3.14 ml of lithium aluminum hydride in toluene was dilutedin a dry flask under N₂ atmosphere with 30 ml of THF. The resultingmixture was cooled to 0° C. and treated dropwise with a solution of 1.43g (6.28 mmol) of ethyl 2-(N,N-diethylamino)thiazole-4-carboxylate in 5ml of THF. After addition, the solution was allowed to warm slowly toambient temperature, stirred for 1 h, recooled to 0° C., and treatedwith a small amount of aqueous Rochelle's salt followed by ethylacetate. After stirring, the slurry was filtered, washed with additionalethyl acetate, and the combined filtrates were concentrated in vacuo.The residue was purified by silica gel chromatography using methanol inchloroform to provide 0.864 g (73%) of the desired compound, R_(f) 0.17(4% methanol in chloroform). Mass spectrum: (M+H)⁺=187.

D. N-((2-(N,N-Diethylamino)-4-thiazolyl)methoxycarbonyl)valine MethylEster

A solution of 5.11 mmol of α-isocyanato-valine methyl ester in 10 ml ofdichloromethane was treated with 0.864 g (4.65 mmol) of2-(N,N-diethylamino)-4-(hydroxymethyl)thiazole and 0.46 mmol of4-dimethylaminopyridine. The resulting solution was stirred at ambienttemperature for 16 h, after which it was diluted with 200 ml ofchloroform, washed successively with 10% citric acid, aqueous NaHCO₃,and saturated brine. After drying over Na₂SO₄, the solvent was removedin vacuo, and the residue was chromatographed on silica gel using 1-2%methanol in chloroform to provide 1.31 g (82%) of the desired compound,R_(f) 0.51 (4% methanol in chloroform) as an oil. ¹H NMR (CDCl₃) δ 0.89(d, J=7 Hz, 3H), 0.96 (d, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 6H), 2.15 (m,1H), 3.51 (q, J=7 Hz, 4H), 3.74 (s, 3H), 4.29 (dd, J=8, 4 Hz, 1H), 5.03(s, 2H), 5.34 (br d, J=8 Hz, 1H), 6.42 (s, 1H). Mass spectrum:(M+H)⁺=344.

E. N-((2-(N,N-Diethylamino)-4-thiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 22D provided thedesired compound.

F.(2S,3S,5S)-5-(N-(N-((2-(N,N-Diethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 22E provided the desiredcompound.

EXAMPLE 23 A. 2-(N,N-Dimethylamino)-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 10 but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-(dimethylamino)thiazole dihydrochloride provided,after silica gel chromatography using first 10% methanol in chloroformfollowed by 4% methanol/2% isopropylamine in chloroform, the desiredcompound, R_(f) 0.05 (10% methanol in chloroform).

¹H NMR (CDCl₃) δ 2.46 (s, 3H), 3.08 (s, 6H), 3.66 (s, 2H), 6.30 (s, 1H).Mass spectrum: (M+H)⁺=172.

B.N-((N-Methyl-N-(((N,N-dimethylamino)-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

A solution of 741 mg (4.42 mmol) of α-isocyanato-L-valine in in 5 ml ofdichloromethane was added to a solution of 720 mg (4.21 mmol) of2-(N,N-dimethylamino)-4-(((N-methyl)amino)methyl)thiazole in 25 ml ofdichloromethane. The resulting solution was stirred at ambienttemperature for 16 h, partitioned between chloroform and aqueous NaHCO₃,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel chromatography using 2% methanol in chloroform to provide463 mg (34%) of the desired compound, R_(f) 0.25 (2% methanol inchloroform). NMR (CDCl₃) δ 0.96 (d, J=7 Hz, 3H), 0.98 (d, J=7 Hz, 3H),2.13 (m, 1H), 2.97 (s, 3H), 3.11 (s, 6H), 3.71 (s, 3H), 4.07 (br d, J=16Hz, 1H), 4.34 (dd, J=9, 5 Hz, 1H), 4.42 (d, J=16 Hz, 1H), 6.29 (s, 1H),6.37 (br, 1H). Mass spectrum: (M+H)⁺=329.

C.N-((N-Methyl-N-(((N,N-dimethylamino)-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 23B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-(((N,N-dimethylamino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 23C provided, after silica gelchromatography, the desired compound.

EXAMPLE 24 A. Ethyl 2-Isopropylthiazole-5-carboxylate

Using the procedure of Example 1J but replacing thioformamide with2-methylpropane-thioamide provided, after silica gel chromatographyusing 9:1 ethyl acetate:hexane, the desired compound, R_(f) 0.8, (5%methanol in chloroform) in 83% yield.

B. 5-(Hydroxymethyl)-2-isopropylthiazole

Using the procedure of Example 5B, but replacing ethyl2-isopropyl-4-thiazolecarboxylate with ethyl2-isopropylthiazole-5-carboxylate provided, after silica gelchromatography using 3% methanol in chloroform, the desired compound,R_(f) 0.3, (5% methanol in chloroform) in 25% yield. ¹H NMR (d₆-DMSO) δ1.30 (d, J=7 Hz, 6H), 3.22 (heptet, J=7 Hz 1H), 4.61 (dd, J=6, 1 Hz,2H), 5.45 (t, J=6 Hz, 1H), 7.48 (br s, 1H).

C. N-((2-Isopropyl-5-thiazolyl)methoxycarbonyl)valine Methyl Ester

Using the procedure of Example 5D but replacing4-(hydroxymethyl)-2-isopropylthiazole with5-(hydroxymethyl)-2-isopropylthiazole provided, after silica gelchromatography using 3% methanol in chloroform, the desired compound,R_(f) 0.8, (5% methanol in chloroform) in 29% yield. ¹H NMR δ 0.89 (d,J=7 Hz, 6H), 0.95 (d, J=7 Hz, 3H), 0.97 (d, J=7 Hz, 3H), 2.14 (m, 1H),3.33 (heptet, J=7 Hz, 1H), 3.74 (s, 3H), 4.30 (dd, J=9, 5 Hz, 1H), 5.23(s, 2H), 5.25 (br d, 1H), 7.63 (s, 1H). Mass spectrum: (M+H)⁺=315.

D. N-((2-Isopropyl-5-thiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 24C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 24D provided the desiredcompound.

EXAMPLE 25 A. 2-Methoxythioacetamide

Using the procedure of Example 1O but replacing isobutyramide with2-methoxyacetamide provided the desired compound in 52% yield.

B. 4-(Chloromethyl)-2-(methoxymethyl)thiazole hydrochloride

Using the procedure of Example 1P but replacing 2-methylpropanethioamidewith 2-methoxythioacetamide provided the crude desired compound in 41%yield.

C. 2-(Methoxymethyl)-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-(methoxymethyl)-thiazole hydrochloride provided,after silica gel chromatography using 3% methanol in chloroform, thedesired compound, R_(f) 0.1, (5% methanol in chloroform) in 73% yield.

D.N-((N-Methyl-N-((2-(methoxymethyl)-4-thiazolyl)methyl)amino)carbonyl)L-valineMethyl Ester

Using the procedure of Example 1S but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-(methoxymethyl)-4-(((N-methyl)amino)methyl)thiazole provided, aftersilica gel chromatography using 3% methanol in chloroform, the desiredcompound, R_(f) 0.5, (5% methanol in chloroform) in 23% yield.

E.N-((N-Methyl-N-((2-(Methoxymethyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 25D provided thedesired compound.

F.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(methoxymethyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 25E provided the desiredcompound.

EXAMPLE 26 A.1,1-Diethoxy-4-((3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy)-2-butyne

A 1 M solution of ethylmagnesium bromide in THF (200 ml, 0.2 mol) wastreated with 29 ml (0.2 mol) of a solution of3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran in toluene, whilemaintaining ambient temperature through use of a cool water bath. Theresulting solution was stirred for 4 h and treated with 47 ml (0.28 mol)of a solution of triethylorthoformate in toluene, while maintainingambient temperature with a cool water bath. The resulting solution washeated to 85° C. for 8 h, allowing the removal of THF by distillation.After being allowed to cool, the resulting solution was poured into 500ml of ice-water containing 29 g of NH₄OAc, extracted with two portionsof ether, dried over K₂CO₃, and concentrated in vacuo. The residue wasdistilled at ca. 0.5 mm Hg pressure (b.p. 103-108° C.) to provide 39.5 g(79%) of the desired compound. ¹H NMR (CDCl₃) δ 1.24 (t, J=7 Hz, 6H),1.5-1.9 (m, 6H), 3.5-3.65 (m, 3H), 3.7-3.9 (m, 3H), 4.32 (AA′, 2H), 4.82(m, 1H), 5.31 (m, 1H). Mass spectrum: (M+NH₄)⁺=260.

B. 5-(Hydroxymethyl)isoxazole

A solution of 39.28 g (161 mmol) of the resultant compound of Example26A and 26 g (376 mmol) of hydroxylamine hydrochloride in 168 ml ofethanol and 34 ml of water was heated at reflux under N₂ atmosphere for1 h. After being allowed to cool, the resulting solution wasconcentrated in vacuo to ⅓ the original volume, diluted with 50 ml ofwater, and extracted with 2 portions, of ether. The combined extractswere concentrated to an oil. The crude product (7.04 g, 44%) wasobtained after distillation (79-84° C., 0.5 mm Hg). Silica gelchromatography using 0-3% methanol in dichloromethane provided 4.9 g ofthe desired compound contaminated with 5-hydroxypentanal oxime. ¹H NMR(CDCl₃) δ 1.95 (br, 1H), 4.81 (s, 2H), 6.27 (d, J=1 Hz, 1H), 8.23 (d,J=1 Hz, 1H). Mass spectrum: (M+NH₄)⁺=117.

C. ((5-Isoxazolyl)methyl)-(4-nitrophenyl)carbonate

Using the procedure of Example 1L, but replacing5-(hydroxymethyl)thiazole with 5-(hydroxymethyl)isoxazole provided,after silica gel chromatography using 8:2 dichloromethane:hexane, thedesired compound.

¹H NMR (CDCl₃) δ 5.41 (s, 2H), 6.46 (d, J=1 Hz, 1H), 7.40 (m, 2H), 8.30(m, 3H). Mass spectrum: (M+NH₄)⁺=282.

D.(2S,3S,5S)-5-Amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A mixture of 1.54 g (5.41 mmol) of(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane and 0.673 g (5.41mmol) of phenylboric acid in anhydrous toluene (130 mL) was heated atreflux under argon for 2 hrs with removal of H₂O by a Dean-Stark trap.The resulting yellow solution was allowed to cool and the solvent wasremoved in vacuo to give an oil which solidified upon standing. Theresidue was taken up in 90 ml of THF, cooled to −40° C., and treateddropwise under Ar atmosphere over a period of 1 h with 1.11 g (3.78mmol) of ((5-isoxazolyl)methyl)-(4-nitrophenyl)carbonate in 40 ml ofTHF. The solution was allowed to warm to −20° C. over the next 0.5 hr,then was stirred at 0° C. for 2.5 hrs and at room temperature for 1 hr.After removal of the solvent in vacuo, the residue was taken up in ethylacetate (200 mL), washed sequentially with 5% aqueous K₂CO₃ (4×25 mL)and saturated brine (25 mL), dried over Na₂SO₄ and concentrated invacuo. Silica gel chromatography of the residue using a gradient ofmethanol in chloroform (2%, 4%, 6%) afforded a mixture of the desiredproduct and its regioisomer. Purification of the mixture on twoconsecutive 250 g SiO₂ columns (deactivated with 1%isopropylamine/CH₂Cl₂) with a gradient of isopropylamine/CH₂Cl₂ (0.5%,1%) afforded the desired compound as a sticky solid (0.730 g, 1.78 mmol,33%): ¹H NMR (DMSO-d₆) δ 1.17-1.57 (m, 5H), 2.56-2.69 (m, 2H), 2.75-2.86(m, 1H), 2.89-3.00 (m, 2H), 3.53-3.71 (m, 3H), 5.06 (s, 2H), 6.32 (d,J=2.4 Hz,1H), 7.11-7.30 (m, 10H), 8.54 (d, J=2.4 Hz, 1H). Mass spectrum:(M+H)⁺=410.

E.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 1% methanol inchloroform, 120 mg (70%) of the desired compound, R_(f) 0.3, (5%methanol in chloroform), as a solid, mp 60-62° C. Mass spectrum:(M+H)⁺=705. Anal. Calcd for C₃₇H₄₈N₆O₆S: C, 63.05; H, 6.86; N, 11.92.Found: C, 62.68; H, 7.00; N, 11.65.

EXAMPLE 27(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valineprovided, after silica gel chromatography using a gradient of 1-4%methanol in dichloromethane, 225 mg (80%) of the desired compound. ¹HNMR (DMSO-d₆) δ 0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H),1.35-1.54 (m, 2H), 1.80-1.95 (m, 1H), 2.55-2.73 (m, 4H), 2.83 (s, 3H),2.94-3.09 (m, 1H), 3.53-3.63 (m, 1H), 3.73-3.86 (m, 1H), 3.92 (t, J=8.4Hz, 1H), 4.08-4.34 (m, 3H), 4.65 (d, J=6 Hz, 1H), 5.04 (s, 2H), 5.91 (d,J=9 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.06-7.27 (m,10H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.52 (d, J=2.4 Hz, 1H). Massspectrum: (M+H)⁺=689; (M+NH₄)⁺=706. Anal. Calcd for C₃₇H₄₈N₆O₇: C,64.52; H, 7.02; N, 12.20. Found: C, 64.52; H, 7.14; N, 12.06.

EXAMPLE 28 A. Ethyl 2-Methylthiazole-5-carboxylate

Using the procedure of Example 1J, but replacing thioformamide withthioacetamide provided the crude desired compound.

B. 5-(Hydroxymethyl)-2-methylthiazole

Using the procedure of Example 1K, but replacing ethylthiazole-5-carboxylate with crude ethyl 2-methylthiazole-5-carboxylateprovided, after silica gel chromatography using 3% then 5% methanol inchloroform, the desired compound, R_(f) 0.27, (4% methanol inchloroform) in 78% yield. ¹H NMR (CDCl₃) δ 2.32 (br, 1H), 2.70 (s, 3H),4.80 (s, 2H), 7.46 (s, 1H). Mass spectrum: (M+H)⁺=130.

C. ((2-Methyl-5-thiazolyl)methyl)-(4-nitrophenyl)carbonate

Using the procedure of Example 1L, but replacing5-(hydroxymethyl)thiazole with 5-(hydroxymethyl)-2-methylthiazoleprovided, after silica gel chromatography using first 1:5chloroform:hexane, then 4% methanol in chloroform, the desired compound,R_(f) 0.46 (20% ethyl acetate in chloroform) in 97% yield.

D.(2S,3S,5S)-5-Amino-2-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-2-Amino-5-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1M, but replacing((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate with((2-methyl-5-thiazolyl)methyl)-(4-nitrophenyl)carbonate provided, aftersilica gel chromatography using 4% methanol in chloroform, a mixture ofthe desired compounds. A second chromatography using 1%-3%isopropylamine in chloroform provided pure(2S,3S,5S)-5-amino-2-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-2-amino-5-(N-((2-methyl-5-thiazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

E.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 210 mg (84%) of the desired compound, R_(f) 0.18, (4%methanol in chloroform). Mass spectrum: (M+H)⁺=735. Anal. Calcd forC₃₈H50N₆O₅S₂. 2H₂O: C, 59.20; H, 7.06; N, 10.90. Found: C, 58.92; H,6.37; N, 10.71.

EXAMPLE 29 A.5-Methyl-1-((3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy)-2-hexyn-4-one

The desired compound was prepared from isobutyryl chloride and3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran by analogy to theprocedure of Tohda, et. al. (Synthesis, 777 (1977)).

B. 5-(Hydroxymethyl)-3-isopropylisoxazole

Using the procedure of Example 26B but replacing the resultant compoundof Example 26A with the resultant compound of Example 29A provided thedesired compound.

C. N-((3-Isopropyl-5-isoxazolyl)methoxycarbonyl)valine Methyl Ester

Using the procedure of Example 5D but replacing4-(hydroxymethyl)-2-isopropylthiazole with5-(hydroxymethyl)-3-isopropylisoxazole provided the desired compound.

D. N-((3-Isopropyl-5-isoxazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 29C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-((3-Isopropyl-5-isoxazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 29D provided the desiredcompound.

EXAMPLE 30 A. 2-Isopropyl-4-(methanesulfonyloxymethyl)thiazole

A solution of 1.2 mmol of 4-(hydroxymethyl)-2-isopropylthiazole and 1.3mmol of diisopropylethylamine in 20 ml of dichloromethane was cooled to−20° C. and treated dropwise with 1.3 mmol of methanesulfonyl chloride.The resulting mixture was stirred for 1 h, quenched with aqueous citricacid, separated, dried over Na₂SO₄, and concentrated in vacuo to providethe desired compound.

B. 2-Isopropyl-4-(mercaptomethyl)thiazole

A mixture of 0.8 mmol of the resultant compound of Example 30A and 1.0mmol of sodium hydrosulfide hydrate in 20 ml of THF was heated at refluxuntil analysis by thin layer chromatography indicated consumption ofstarting material. The resulting mixture was allowed to cool,concentrated in vacuo, partitioned between dichloromethane and water,dried over Na₂SO₄, and concentrated to provide the crude desiredcompound.

C. N-((2-Isopropyl-4-thiazolyl)thiomethoxycarbonyl)valine Methyl Ester

Using the procedure of Example 5D, but replacing4-(hydroxymethyl)-2-isopropylthiazole with the resultant compound ofExample 30B provided, after chromatography on silica gel, the desiredcompound.

D. N-((2-Isopropyl-4-thiazolyl)thiomethoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 30C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)thiomethoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 30D provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 31 A. 2-Isopropylthiazole-4-carboxaldehyde

A solution of 3.1 g (15.6 mmol) of ethyl2-isopropylthiazole-4-carboxylate in 50 ml of dichloromethane was cooledunder N₂ atmosphere to −78° C. and treated dropwise with 15.6 ml (23.4mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene overa period of 1.5 h. After being stirred for an additional 0.5 h, thesolution was quenched with 5 ml of methanol followed by 15 ml of aqueousRochelle's salt. The resulting mixture was partitioned betweenchloroform and aqueous Rochelle's salt, dried over Na₂SO₄, andconcentrated to provide 1.37 g (56%) of the crude desired compound,R_(f) 0.47 (20% ethyl acetate in hexane). ¹H NMR (CDCl₃) δ 1.45 (d, J=7Hz, 6H), 3.39 (heptet, J=7 Hz, 1H), 8.07 (s, 1H), 10.00 (s, 1H). Massspectrum: (M+H)⁺=156.

B. (E)-Ethyl 3-(2-Isopropyl-4-thiazolyl)propenoate

A slurry of 60% NaH (18 mmol) in mineral oil was washed with hexane,decante under N₂ atmosphere, and diluted with 25 ml of THF. Theresulting mixture was cooled to 0° C., treated portionwise with 3.24 ml(16.4 mmol) of triethylphosphonoacetate. After addition, the solutionwas stirred for 10 min, treated with 1.37 g (8.84 mmol) of2-isopropylthiazole-4-carboxaldehyde in 25 ml of THF, allowed to warm toambient temperature for 25 min, and quenched with 100 ml of saturatedaqueous NH₄Cl. The mixture was extracted with three 100 ml portions ofethyl acetate, dried over Na₂SO₄, and concentrated in vacuo. Silica gelchromatography of the residue using 5-10% ethyl acetate in hexaneprovided 1.61 g (81%) of the desired compound, R_(f) 0.64 (20% ethylacetate in hexane). ¹H NMR (CDCl₃) δ 1.33 (t, J=7 Hz, 3H), 1.42 (d, J=7Hz, 6H), 3.32 (heptet, J=7 Hz, 1H), 4.26 (q, J=7 Hz, 2H), 6.75 (d, J=15Hz, 1H) 7.29 (s, 1H), 7.57 (d, J=15 Hz, 1H).

C. Methyl 3-(2-isopropyl-4-thiazolyl)propanoate

A solution of 225 mg (1 mmol) of (E)-ethyl3-(2-isopropyl-4-thiazolyl)propenoate in 10 ml of freshly distilled(from calcium hydride) methanol and 1 ml of dry THF was treated with 49mg (2 mmol) of magnesium turnings. The mixture was stirred for 20 min,during which the magnesium was consumed. The resulting solution waspoured over cold aqueous HCl, basified to pH 8 with NaHCO₃, extractedwith ethyl acetate, dried over Na₂SO₄, and concentrated. Silica gelchromatography using 10% ethyl acetate in hexane provided a mixture ofthe desired compound and methyl 3-(2-isopropyl-4-thiazolinyl)propanoate.

D. 3-(2-Isopropyl-4-thiazolyl)propanoic Acid

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 31C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-(tert-Butyloxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith N-(tert-butyloxycarbonyl)-L-valine provided, after purification bysilica gel chromatography, the desired compound.

F.(2S,3S,5S)-5-(N-(Valinylamino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 0.1 mmol of the resultant compound of Example 31E wastreated with 10 ml of 4N HCl in dioxane, stirred at 0° C. for 1 h,concentrated in vacuo, partitioned between chloroform and aqueousNaHCO₃, dried over Na₂SO₄, and concentrated to provide the crude desiredcompound.

G.(2S,3S,5S)-5-(N-(N-(3-(2-Isopropyl-4-thiazolyl)propanoyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 31D and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 31F provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 32 A. Thiazole-5-carboxaldehyde

Using the procedure of Example 16A but replacing ethyl2-isopropyl-4-thiazole carboxylate with ethyl thiazole-5-carboxylateprovided the desired compound.

B. 5-(1-Hydroxyethyl)thiazole

Using the procedure of Example 16B but replacing the resultant compoundof Example 16A with the resultant compound of Example 32A provided thedesired compound.

C. (1-(5-Thiazolyl)ethyl)-(4-nitrophenyl)carbonate

Using the procedure of Example 1L but replacing5-(hydroxymethyl)thiazole with the resultant compound of Example 32Bprovided the desired compound.

D.(2S,3S,5S)-5-Amino-2-(N-(1-(5-thiazolyl)ethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 19F but replacing((5-oxazolyl)methyl)-(4-nitrophenyl)carbonate with(1-(5-thiazolyl)ethyl)-(4-nitrophenyl)carbonate provided, afterpurification by silica gel chromatography, the desired compound.

E.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(1-(5-thiazolyl)ethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 32D provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 33 A. ((5-Isothiazolyl)methyl)-(4-nitrophenyl)carbonate

Using the procedure of Example 1L but replacing5-(hydroxymethyl)thiazole with 5-(hydroxymethyl)isothiazole (Bennett,et. al., J. Chem. Soc., 3834 (1965)) provided the desired compound.

B.(2S,3S,5S)-5-Amino-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 19F but replacing((5-oxazolyl)methyl)-(4-nitrophenyl)carbonate with((5-isothiazolyl)methyl)-(4-nitrophenyl)carbonate provided, afterpurification by silica gel chromatography, the desired compound.

C.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 33B provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 34 A. (2S,3R,4R,5S)-2,5-Diamino-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1F but replacing the resultant compoundof Example 1E with(2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexaneprovided the crude desired compound mixed with benzyl alcohol in 92%yield. Purification of a sample was achieved by silica gelchromatography using 2% isopropylamine in chloroform. ¹H NMR (CDCl₃) δ2.71 (dd, J=13, 9 Hz, 2H), 2.92 (dd, J=13, 5 Hz, 2H), 3.03 (dd, J=9, 5Hz; 2H), 3.68 (s, 2H), 7.15-7.35 (m, 10H). Mass spectrum: (M+H)⁺=301.

B.(2S,3R,4R,5S)-2-Amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1M but replacing(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane with(2S,3R,4R,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane provided,after silica gel chromatography, the desired compound.

C.(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 34B provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 35 A. (2S,3S,5S)-2,5-Diamino-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1F but replacing the resultant compoundof Example 1E with(2S,3S,4S,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexaneprovided the desired compound. ¹H NMR (CDCl₃) δ 2.63 (dd, J=14, 11 Hz,2H), 2.85 (dd, J=14, 4 Hz, 2H), 3.60 (dt, J=11, 4 Hz, 2H), 3.92 (d, J=3Hz, 2H), 7.2-7.4 (m, 10H). Mass spectrum: (M+H)⁺=301.

B.(2S,3S,4S,5S)-2-Amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1M but replacing(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane with(2S,3S,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane provided,after silica gel chromatography, the desired compound.

C.(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 35B provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 36 A.(4S,5S,1′R,2′S)-5-(1-Acetoxy-2-(N-((((benzyl)oxy)carbonyl)amino))-3-phenylpropyl)-4-benzyl-oxazolidin-2-one

A suspension of 5.02 g (8.80 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexanein 400 ml of acetonitrile was treated dropwise with 3 ml (20 mmol) ofα-acetoxyisobutyryl bromide. The resulting solution was stirred under N₂atmosphere at ambient temperature for 2 h, filtered to remove traces ofsolid starting material, quenched cautiously with 100 ml of aqueousNaHCO₃, and concentrated in vacuo to a volume of 100 ml. The resultingmixture was extracted with two 100 ml portions of dichloromethane, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified bysilica gel chromatography using first 10% then 25% ethyl acetate indichloromethane to provide 3.15 g (71%) of the desired compound as awhite foam. ¹H NMR (CDCl₃) δ 2.09 (s, 3H), 2.53 (br t, J=12 Hz, 1H),2.72 (dd, J=13, 3 Hz, 1H), 2.83 (dd, J=14, 8 Hz, 1H), 2.95 (dd, J=14, 7Hz, 1H), 3.95 (m, 1H), 4.45 (m, 1H), 4.8 (m, 2H), 5.0-5.1 (m, 3H), 5.29(dd, J=9, 3 Hz, 1H), 7.0-7.4 (m, 10H). Mass spectrum: (M+NH₄)⁺=520.

B. (2S,3R,4S,5S)-2,5-Diamino-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1F but replacing the resultant compoundof Example 1E with(4S,5S,1′R,2′S)-5-(1-acetoxy-2-(N-(benzyloxycarbonylamino))-3-phenylpropyl)-4-benzyl-oxazolidin-2-oneprovided the desired compound mixed with benzyl alcohol. Purification ofa small portion by silica gel chromatography using 5% methanol/2%isopropylamine in chloroform provided the pure desired compound., m.p.115-119° C. ¹H NMR (CDCl₃) δ 2.46 (dd, J=14, 9 Hz, 1H), 2.61 (dd, J=14,11 Hz, 1H), 3.02 (td, J=9, 3 Hz, 1H), 3.19 (dd, J=14, 4 Hz, 1H),3.35-3.4 (m, 2H), 3.51 (t, J=9 Hz, 1H), 3.76 (dd, J=9, 3 Hz, 1H),7.2-7.4 (m, 10H).

C.(2S,3R,4S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 0.133 mmol of(2S,3R,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane and 0.147mmol of ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 10 ml oftetrahydrofuran was stirred at ambient temperature for 16 h. Theresulting solution was diluted with 50 ml of chloroform, washed withseveral portions of 3N aqueous NaOH, dried over Na₂SO₄, and concentratedin vacuo. Silica gel chromatography of the residue provided the desiredcompound.

D.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 36C provided, after purificationby silica gel chromatography, the desired compound.

EXAMPLE 37 A.(2S,3R,4S,5S)-2-Amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith (2S,3R,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexaneprovided, after purification by silica gel chromatography, the desiredcompound.

B.(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 36C but replacing(2S,3R,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane with theresultant compound of Example 37A provided, after purification by silicagel chromatography, the desired compound.

EXAMPLE 38 A. 5-(Hydroxymethyl)-3-isopropylisothiazole

The desired compound was prepared from the resultant compound of Example29A using the procedure of Lucchesini, et. al. (Heterocycles, 29, 97(1989)).

B. N-((3-Isopropyl-5-isothiazolyl)methoxycarbonyl)valine Methyl Ester

Using the procedure of Example 5D but replacing4-(hydroxymethyl)-2-isopropylthiazole with5-(hydroxymethyl)-3-isopropylisothiazole provided the desired compound.

C. N-((3-Isopropyl-5-Isothiazolyl)methoxycarbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 38B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((3-Isopropyl-5-isothiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith the resultant compound of Example 38C provided the desiredcompound.

EXAMPLE 39(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 20 mg (80%) of the desired compound, R_(f) 0.23, (4%methanol in chloroform). Mass spectrum: (M+H)⁺=735. Anal. Calcd forC₃₈H₅₀N₆O₅S₂.2H₂O: C, 59.20; H, 7.06; N, 10.90. Found: C, 59.13; H,6.42; N, 10.82.

EXAMPLE 40 Following the procedures of the above Examples, the followingcompounds can be prepared.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-isothiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclohexyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,1-dimethyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valiny)amino)-2-(N-5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclopentenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclohexenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclopentenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclohexenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,2-dimethyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclopentyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclohexyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-benzyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl-1-ethenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,8S,5S)-5-(N-(N-((N-Methyl-N-((2-(4-fluoro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-chloro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-methoxy)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-methoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyloxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(N,N-dimethylamino)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-ethyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclohexyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(l,1-dimethyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclopentenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclohexenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclopentenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclohexenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,2-dimethyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclopentyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclohexyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-benzyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl-1-ethenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(4-fluoro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-chloro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-methoxy)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-methoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyloxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(N,N-dimethylamino)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-ethyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclohexyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,1-dimethyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclopentenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-cyclohexenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclopentenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-cyclohexenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-methyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1,2-dimethyl-1-propenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclopentyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(cyclohexyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-benzyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl)ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-phenyl-1-ethenyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(4-fluoro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-chloro)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-methoxy)phenyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(2-thiazolyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-methoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethoxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyloxy-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(N,N-dimethylamino)methyl-4-thiazolyl)methyl(amino(carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)5-(N-(N-((N-Methyl-N-((2-(2-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-methyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-ethyl)propyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Ethyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((3-Isopropyl-5-isoxazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Ethyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((3-Isopropyl-5-isoxazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)alaninyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Ethyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)alaninyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(N,N-Dimethylamino)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(4-Morpholinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2-(N-(N-((2-(1-Pyrrolidinyl)-4-thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((3-Isopropyl-5-isoxazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isothiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

EXAMPLE 41(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedures of Example 18A-F, but replacing isobutyramide withpropionamide, provided the desired compound. ¹H NMR (DMSO-d₆) δ 0.74 (d,J=6 Hz, 6H),1.19 (t, J=7 Hz, 3H), 1.38-1.51 (m, 2H), 1.80-1.94 (m, 1H),2.54-2.74 (m, 5H), 2.83 (s, 3H), 3.53-3.63 (m, 1H), 3.82 (br q, 1H),3.92 (t, J=8 Hz, 1H), 4.13, (m, 1H), 4.26 (AA′, 2H), 4.63 (d, J=6 Hz,1H), 5.13 (AA′, 2H), 5.90 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H),7.07-7.25 (m, 12H), 7.68 (d, J=8.7 Hz, 1H), 7.77 (s, 1H), 7.86 (s, 1H),9.05 (s, 1H). Mass spectrum: (M+H)⁺=691. Anal. Calcd forC₃₆H₄₆N₆O₆S,0.3H₂O: C, 62.10; H, 6.75; N, 12.07. Found: C, 62.42; H,6.68; N, 11.69.

EXAMPLE 42(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-methyl-4-oxazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedures of Example 18A-F, but replacing isobutyramide withacetamide, provided the desired compound. Mass spectrum: (M+H)⁺=677.

EXAMPLE 43(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-oxazolyl)-3-hydroxyhexane

Using the procedures of Example 8C-8K, but replacing5-chloromethylthiazole hydrochloride with 5-chloromethyloxazolehydrochloride provided the desired compound.

EXAMPLE 44 A. 2-Ethylbutanamide

A solution of 21.5 ml of oxalyl chloride (2M, 43 mmol) indichloromethane was treated with 5.0 g (43 mmol) of 2-ethylbutyric acidfollowed by 0.1 ml of dimethylformamide. The resulting solution wasstirred at ambient temperature for 1 h, during which gas evolution wasobserved. After the termination of gas evolution, the solution wasconcentrated in vacuo to give crude 2-ethylbutyryl chloride. The crudeacid chloride was taken up in 200 ml of acetone and treated with 4.6 g(60 mmol) of ammonium acetate. The resulting mixture was stirred atambient temperature for 1 h, filtered, and concentrated in vacuo toprovide 4.2 g (85%) of the desired compound. ¹H NMR (d₆-DMSO) δ 0.80 (t,J=7 Hz, 6H), 1.32 (m, 2H), 1.45 (m, 2H), 1.93 (m, 1H), 6.71 (br, 1H),7.23 (br, 1H).

B. 2-Ethylbutane-thioamide

Using the procedure of Example 1O, but replacing isobutyramide with2-ethylbutanamide provided 1.6 g (25%) of the crude desired compound.

C. 4-(Chloromethyl)-2-(3-pentyl)thiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with 2-ethylbutane-thioamide provided the crudedesired compound as a yellow oil.

D. 2-(3-Pentyl)-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-(3-pentyl)thiazole hydrochloride provided, afterpurification of the residue by silica gel chromatography using 5%methanol in chloroform, 1.5 g (71%) of the desired compound.

E.N-((N-Methyl-N-((2-(3-pentyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-(3-pentyl)-4-(((N-methyl)amino)methyl)thiazole provided, afterpurification by silica gel chromatography using 3% methanol inchloroform as an eluent, 1.6 g (61%) of the desired compound.

F.N-((N-Methyl-N-((2-(3-pentyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 44E provided 0.4 g(52%) of the desired compound.

G.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(3-pentyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-(3-pentyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 99:1CHCl₃:CH₃OH, 72 mg (41%) of the desired compound (R_(f) 0.3, 95:5CHCl₃:CH₃OH) as a solid, mp 64-66° C. Mass spectrum: (M+H)⁺=749. Anal.Calcd for C₃₉H₅₂N₆O₅S₂: C, 62.54; H, 7.00; N, 11.22; S, 8.56. Found: C,62.67; H, 6.85; N, 11.06; S, 8.45.

EXAMPLE 45 A.(((2-Isopropyl)-5-thiazolyl)methyl)-(4-nitrophenyl)carbonate

Using the procedure of Example 1L, but replacing 5-(hydroxymethyl)thiazole with 5-(hydroxymethyl)-2-isopropylthiazole provided, afterpurification by silica gel chromatography using 1% MeOH/CHCl₃, 0.7 g(78%) of the desired compound, R_(f=)0.8 (5% MeOH/CHCl₃).

B.(2S,3S,5S)-5-Amino-2-(N-(((2-isopropyl)-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1N, but replacing((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate with(((2-isopropyl)-5-thiazolyl)methyl)-(4-nitrophenyl)carbonate provided,after purification by silica gel chromatography using 99:2:1CHCl₃:isopropylamine:CH₃OH, R_(f)=0.2, 0.17 g (18%) of the desiredcompound, (1% isopropylamine in CHCl₃). ¹H NMR (d₆-DMSO) δ 1.38 (d, J=7Hz, 6H), 1.43 (m, 1H), 1.64 (m, 1H), 2.46 (dd, J=14, 8 Hz, 1H), 2.63 (m,2H), 2.80 (dd, J=14, 5 Hz, 1H), 2.94 (m, 1H), 3.21 (m, 1H), 3.64 (m,2H), 5.09 (AA′, 2H), 6.98 (d, J=9 Hz, 1H), 7.1-7.3 (m, 10H), 7.60 (s,1H). Mass spectrum: (M+H)⁺=468.

C.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(((2-isopropyl)-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-(((2-isopropyl)-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after purification by silica gel chromatography using 99:1CHCl₃:CH₃OH, 50 mg (61%) of the desired compound (R_(f) 0.28, 95:5CHCl₃:CH₃OH) as a solid, mp 64-66° C. Mass spectrum: (M+H)⁺=764. Anal.Calcd for C₄₀H₅₄N₆O₅S₂: C, 62.97; H, 7.13; N, 11.01. Found: C, 62.91; H,7.11; N, 10.81.

EXAMPLE 46 A. 1-(Aminothiocarbonyl)pyrrolidine

A solution of 1.0 g (14 mmol) of pyrrolidine in 70 ml of tetrahydrofuranwas treated dropwise with 2.0 ml of trimethylsilylisocyanate. Theresulting solution was stirred at ambient temperature for two days, andconcentrated in vacuo. Purification of the residue by silica gelchromatography using 4% methanol in chloroform provided the desiredcompound (R_(f) 0.5, 10% methanol in chloroform).

B. (4-(Chloromethyl)-2-(1-pyrrolidinyl)thiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with 1-(aminothiocarbonyl)pyrrolidine providedthe crude desired compound.

C. (2-(1-Pyrrolidinyl)-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-(1-pyrrolidinyl)thiazole hydrochloride provided,after purification of the residue by silica gel chromatography using 2%isopropylamine/2% methanol in chloroform, 0.89 g (30%) of the desiredcompound. ¹H NMR (CDCl₃) δ 2.02 (m, 4H), 2.61 (s, 3H), 3.44 (m, 4H),3.90 (s, 2H), 4.84 (br, 1H), 6.51 (s, 1H). Mass spectrum: (M+H)⁺=198.

D.N-((N-Methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-(1-pyrrolidinyl)-4-(((N-methyl)amino)methyl)thiazole provided, afterpurification by silica gel chromatography using 4% methanol inchloroform as an eluent, 0.63 g (39%) of the desired compound. ¹H NMR(CDCl₃) δ 0.96(t, J=7 Hz, 3H), 0.98 (t, J=7 Hz, 3H), 2.04 (m, 4H), 2.14(heptet, J=7 Hz, 1H), 2.97 (s, 3H), 3.45 (m, 4H), 3.71 (s, 3H), 4.10 (m,1H), 4.33 (dd, J=9, 6 Hz, 1H), 4.42 (br d, J=16 Hz, 1H), 6.26 (s, 1H),6.45 (br, 1H). Mass spectrum: (M+H)⁺=355.

E.N-((N-Methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 46D provided 0.24 g(96%) of the desired compound.

F.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 2%methanol in chloroform, the desired compound (R_(f) 0.29, 4% methanol inchloroform). Mass spectrum: (M+H)⁺=748.

EXAMPLE 47 A. Ethyl 2-(2-Isopropyl-4-thiazolyl)acetate

Using the procedure of Example 1P, but replacing 1,3-dichloroacetonewith ethyl 4-chloroacetoacetate provided, after purification by silicagel chromatography using CHCl₃, the desired compound in 34% yield. ¹HNMR (d₆-DMSO) δ 1.18 (t, J=7 Hz, 3H), 1.30 (d, J=7 Hz, 6H), 3.24(heptet, J=7 Hz, 1H), 3.76 (s, 2H), 4.09 (q, J=7 Hz, 2H), 7.31 (s, 1H).Mass spectrum: (M+H)⁺=214.

B. (4-(2-Hydroxyethyl)-2-isopropylthiazole

Using the procedure of Example 5B, but replacing ethyl2-isopropyl-4-thiazolecarboxylate with ethyl2-(2-isopropyl-4-thiazolyl)acetate provided, after purification of theresidue by silica gel chromatography using 2% methanol in chloroform,0.9 g (47%) of the desired compound. ¹H NMR (CDCl₃) δ 1.40 (d, J=7 Hz,6H), 2.95 (t, J=6 Hz, 2H), 3.30 (heptet, J=7 Hz, 1H), 3.92 (t, J=6 Hz,2H), 6.83 (s, 1H). Mass spectrum: (M+H)⁺=172.

C. N-((2-(2-Isopropyl-4-thiazolyl)ethoxy)carbonyl)valine Methyl Ester

Using the procedure of Example 5D, but replacing4-(hydroxymethyl)-2-isopropylthiazole with4-(2-hydroxyethyl)-2-isopropylthiazole provided, after purification bysilica gel chromatography using 3% methanol in chloroform as an eluent,0.8 g (52%) of the desired compound.

D. N-((2-(2-Isopropyl-4-thiazolyl)ethoxyl)carbonyl)valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 47C provided 0.17 g(82%) of the desired compound.

E.(2S,3S,5S)-5-(N-(N-((2-(2-Isopropyl-4-thiazolyl)ethoxy)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith N-((2-(2-isopropyl-4-thiazolyl)ethoxy)carbonyl)valine provided,after purification by silica gel chromatography using 99:1 CHCl₃:CH₃OH,80 mg (47%) of the desired compound (R_(f) 0.3, 95:5 CHCl₃:CH₃OH) as asolid, mp 146-147° C. Mass spectrum: (M+H)⁺=722. Anal. Calcd forC₃₇H₄₇N₅O₆S₂: C, 61.56; H, 6.56; N, 9.70. Found: C, 61.24; H, 6.48, N,9.53.

EXAMPLE 48 E.(2S,3S,5S)-2-(N-(N-((2-(2-Isopropyl-4-thiazolyl)ethoxy)carbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith N-((2-(2-isopropyl-4-thiazolyl)ethoxy)carbonyl)valine and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after purification by silica gel chromatography using 99:1CHCl₃:CH₃OH, 50 mg (30%) of the desired compound (R_(f) 0.3, 95:5CHCl₃:CH₃OH) as a solid, mp 159-160° C. Mass spectrum: (M+H)⁺=722 HRMS.Exact mass calcd for C₃₇H₄₇N₅O₆S₂: 722.3046. Found: 722.3036.

EXAMPLE 49(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valineand replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after purification by silica gel chromatography using 2%methanol in chloroform, the desired compound (R_(f) 0.30, 4% methanol inchloroform).

EXAMPLE 50 A.(2S,3S,5S)-5-(N-(N-(t-Butyloxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith N-(t-butyloxycarbonyl)valine provided, after silica gelchromatography using 1% methanol in chloroform, the desired compound(R_(f) 0.31, 4% methanol in chloroform).

B.(2S,3S,5S)-5-(N-(Valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneHydrochloride

To 135 mg (0.27 mmol) of(2S,3S,5S)-5-(N-(N-(t-butyloxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewas added 8 ml of 4M HCl in dioxane. The resulting mixture was stirredat ambient temperature for 1 h and concentrated in vacuo to provide thecrude desired compound.

C. (2-(2-Isopropyl-4-thiazolyl)acetic Acid

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 47A provided 0.24 g(55%) of the desired compound. ¹H NMR (CDCl₃) δ 1.93 (d, J=7 Hz, 6H),3.35 (heptet, J=7 Hz, 1H), 3.86 (s, 2H), 7.00 (s, 1H). Mass spectrum:(M+H)⁺=186.

D.(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)acetyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith 2-(2-isopropyl-4-thiazolyl)acetic acid provided, after purificationby silica gel chromatography using 99:1 CHCl₃:CH₃OH, 120 mg (80%) of thedesired compound (R_(f) 0.6, 95:5 CHCl₃:CH₃OH) as a solid, mp 153-155°C. Mass spectrum: (M+H)⁺=692. Anal. Calcd for C₃₆H₄₅N₅O₅S₂·0.5H₂O: C,61.69; H, 6.62; N, 9.99; S, 9.15. Found: C,61.92; H, 6.49; N, 10.06; S,8.81.

EXAMPLE 51 A. Cyclopropanecarboxamide

Using the procedure of Example 44A but replacing 2-ethylbutyric acidwith cyclopropanecarboxylic acid provided 6.4 g (50%) of the crudedesired compound.

B. Cyclopropanethiocarboxamide

Using the procedure of Example 1O, but replacing isobutyramide withcyclopropanecarboxamide provided 7.2 g (96%) of the crude desiredcompound.

C. (4-(Chloromethyl)-2-cyclopropylthiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with cyclopropanethiocarboxamide provided thecrude desired compound as a yellow oil.

D. (2-Cyclopropyl-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-cyclopropylthiazole hydrochloride provided, afterpurification of the residue by silica gel chromatography using 5%methanol in chloroform, 0.5 g (25%) of the desired compound.

E.N-((N-Methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-cyclopropyl-4-(((N-methyl)amino)methyl)thiazole provided, afterpurification by silica gel chromatography using 1% methanol/chloroformas an eluent, 0.4 g (48%) of the desired compound.

F.N-((N-Methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 51E provided 0.16 g(70%) of the desired compound.

G.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-cyclopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1%methanol in chloroform, 90 mg (54%) of the desired compound (R_(f) 0.2,95:5 CHCl₃CH₃OH) as a solid, mp 70-71° C. Mass spectrum: (M+H)⁺ =719.Anal. Calcd for C ₃₇H₄₆N₆O₅S₂: C, 61.82; H, 6.45; N, 11.69. Found: C,61.50; H, 6.46; N, 11.41.

EXAMPLE 52 A. Cyclobutanecarboxamide

Using the procedure of Example 44A but replacing 2-ethylbutyric acidwith cyclobutanecarboxylic acid provided 7.5 g (76%) of the crudedesired compound.

B. Cyclobutanethiocarboxamide

Using the procedure of Example 1O, but replacing isobutyramide withcyclobutanecarboxamide provided 6.9 g (80%) of the crude desiredcompound.

C. (4-(Chloromethyl)-2-cyclobutylthiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with Cyclobutanethiocarboxamide provided thecrude desired compound as a yellow oil.

D. (2-Cyclobutyl-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-cyclobutylthiazole hydrochloride provided, afterpurification of the residue by silica gel chromatography using 5%methanol in chloroform, 1.0 g (36%) of the desired compound.

E.N-((N-Methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-cyclobutyl-4-(((N-methyl)amino)methyl)-thiazole provided, afterpurification by silica gel chromatography using 1% methanol inchloroform as an eluent, 0.54 g (31%) of the desired compound. Massspectrum: (M+H)⁺=340.

F.N-((N-Methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 52E provided 0.2 g(42%) of the desired compound.

G.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-cyclobutyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1%methanol in chloroform, 110 mg (64%) of the desired compound (R_(f)0.17, 95:5 CH₂Cl₂:CH₃OH) as a solid, mp 74-76° C. Mass spectrum:(M+H)⁺=733. Anal. Calcd for C₃₈H₄₈N₆O₅S₂: C, 62.27; H, 6.60; N, 11.47;S, 8.75. Found, C, 62.02; H, 6.73; N, 11.33; S, 8.51.

EXAMPLE 53 A. Propanethioamide

Using the procedure of Example 1O, but replacing isobutyramide withpropionamide provided 4.6 g (38%) of the crude desired compound.

¹H NMR (CDCl₃) δ 1.33 (t, J=7 Hz, 3H), 2.70 (q, J=7 Hz, 2H), 6.9 (br,1H), 7.6 (br, 1H). Mass spectrum: (M+H)⁺=90.

B. (4-(Chloromethyl)-2-ethylthiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with propanethioamide provided the crudedesired compound as a yellow oil.

C. (2-Ethyl-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-ethylthiazole hydrochloride provided 1.0 g (52%) ofthe desired compound.

D. N-((N-Methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-ethyl-4-(((N-methyl)amino)methyl)thiazole provided, after purificationby silica gel chromatography using 1% methanol in chloroform as aneluent, 0.7 g (35%) of the desired compound.

E. N-((N-Methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 53D provided 0.28 g(43%) of the desired compound.

F.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-ethyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1%methanol in chloroform, 60 mg (40%) of the desired compound (R_(f) 0.14,95:5 CH₂Cl₂:CH₃OH) as a solid, mp 70-71° C. Mass spectrum: (M+H)⁺=707.Anal. Calcd for C₃₆H₄₆N₆O₅S₂.H₂O: C, 59.65; H, 6.67; N, 11.59. Found: C,59.64; H, 6.59; N, 11.88.

EXAMPLE 54 A. (2-Isopropyl-4-(((N-(1-propyl))amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing 40% aqueous methylaminewith 1-aminopropane provided the crude desired compound.

¹H NMR (CDCl₃) δ 0.94 (t, J=7 Hz, 3H), 1.39 (d, J=7 Hz, 6H), 1.54(sextet, J=7 Hz, 2H), 2.62 (t, J=7 Hz, 2H), 3.30 (heptet, J=7 Hz, 1H),3.87 (d, J=1 Hz, 2H), 6.93 (s, 1H). Mass spectrum: (M+H)⁺=199.

B.N-((N-(1-Propyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isopropyl-4-(((N-(1-propyl))amino)methyl)thiazole provided, aftersilica gel chromatography using 1% methanol in chloroform as an eluent,1.55 g (63%) of the desired compound. ¹H NMR (CDCl₃) δ 0.86 (t, J=7 Hz,3H), 1.38 (d, J=7 Hz, 6H), 1.41 (d, J=7 Hz, 6H), 1.56 (m, 1H), 1.57(sextet, J=7 Hz, 2H), 3.27 (heptet, J=7 Hz, 1H), 3.29 (t, J=7 Hz, 2H),3.71 (s, 3H), 4.45 (m, 3H), 6.31 (br, 1H), 6.98 (s, 1H). Mass spectrum:(M+H)⁺=328.

C.N-((N-(1-Propyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 54B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-(1-Propyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-(1-propyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after silica gel chromatography using 1% methanol inchloroform, 60 mg (44%) of the desired compound (R_(f) 0.3, 95:5CHCl₃:CH₃OH) as a solid, mp 62-64° C. Mass spectrum: (M+H)⁺=721. Anal.Calcd for C₃₇H₄₈N₆O₅S₂.0.5H₂O: C, 60.88; H, 6.77: N, 11.51. Found: C,60.66; H, 6.95; N, 11.45.

EXAMPLE 55 A. (2-Isopropyl-4-((N-(isobutyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing 40% aqueous methylaminewith isobutylamine provided the crude desired compound. Mass spectrum:(M+H)⁺=213.

B.N-((N-(Isobutyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isopropyl-4-(((N-(isobutyl))amino)methyl)thiazole provided, aftersilica gel chromatography using 1% methanol in chloroform as an eluent,0.7 g (41%) of the desired compound.

¹H NMR (DMSO-d₆) δ 0.78 (d, J=7 Hz, 3H), 0.79 (d, J=7 Hz, 3H), 1.30 (m,12H), 1.89 (m, 2H), 3.05 (d, J=8 Hz, 2H), 3.22 (m, 1H), 3.58 (s, 3H),4.13 (m, 1H), 4.44 (AA′, 2H), 6.87 (br d, 1H), 7.23 (s, 1H). Massspectrum: (M+H)⁺=3.42.

C.N-((N-(Isobutyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 55B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-(Isobutyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-(isobutyl)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after silica gel chromatography using 1% methanol inchloroform, 70 mg (50%) of the desired compound (R_(f) 0.3, 5% methanolin chloroform) as a solid, mp 60-61° C. Mass spectrum: (M+H)⁺=735. Anal.Calcd for. C₃₈H₅₀N₆O₅S₂: C, 62.10; H, 6.86; N, 11.43; S, 8.72. Found: C,61.74; H, 7.16; N, 11.36; S, 8.48.

EXAMPLE 56 A.N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isopropyl-4-(((N-methyl)amino)methyl)-oxazole and relacingN-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester withN-(((4-nitrophenyl)oxy)carbonyl)-L-alanine methyl ester provided thedesired compound in 66% yield. ¹H NMR (CDCl₃) δ 1.32 (d, 6H), 1.42 (d,3H), 2.96 (s, 3H), 3.05 (m, 1H), 3.75 (s, 3H), 4.30 (s, 2H), 4.47 (m,1H), 5.80 (br d, 1H), 7.46 (s, 1H). Mass spectrum: (M+H)⁺=284.

B.N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 56A provided thedesired compound.

C.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alaninyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanineprovided, after silica gel chromatography using 92:8 CH₂Cl₂:CH₃OH, thedesired compound (R_(f) 0.49, 92:8 CH₂Cl₂:CH₃OH) in 75% yield. Massspectrum: (M+H)⁺=677.

EXAMPLE 57(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alaninyl)amino)-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanineand replacing2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 92:8 CH₂Cl₂:CH₃OH, thedesired compound (R_(f) 0.48, 92:8 CH₂Cl₂:CH₃OH) in 64% yield. ¹H NMR(DMSO-d₆) δ 1.08 (d, 3H), 1.24 (d, 6H), 1.50 (m, 2H), 2.82 (s, 3H), 3.0(m, 1H), 4.25 (s, 2H), 4.60 (d, 1H), 5.05 (s, 2H), 6.20 (br d, 1H), 6.32(d, 1H), 7.20 (m, 11H), 7.50 (br d, 1H), 7.78 (s, 1H), 8.51 (d, 1H).Mass spectrum: (M+H)⁺=661.

EXAMPLE 58 A. Cyclopentanecarboxamide

Using the procedure of Example 44A but replacing 2-ethylbutyric acidwith cyclopentanecarboxylic acid provided 2.6 g (100%) of the crudedesired compound.

B. Cyclopentanecarboxamide

Using the procedure of Example 1O, but replacing isobutyramide withcyclopentanecarboxamide provided 2.4 g (83%) of the crude desiredcompound.

C. (4-(Chloromethyl)-2-cyclopentylthiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with cyclopentanethiocarboxamide provided thecrude desired compound as a yellow oil.

D. (2-Cyclopentyl-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-cyclopentylthiazole hydrochloride provided, afterpurification of the residue by silica gel chromatography using 3%methanol in chloroform, 0.83 g (43%) of the desired compound.

E.N-((N-Methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-cyclopentyl-4-(((N-methyl)amino)methyl)-thiazole provided, afterpurification by silica gel chromatography using 1% methanol inchloroform as an eluent, 0.77 g (51%) of the desired compound. ¹H NMR(CDCl₃) δ 0.93 (d, J=7 Hz, 3H), 0.97 (d, J=7 Hz, 3H), 1.6-1.9 (m, 6H),2.2 (m, 3H), 2.99 (s, 3H), 3.40 (m, 1H), 3.71 (s, 3H), 4.37 (dd, J=9, 5Hz, 1H), 4.45 (AA′, 2H), 5.99 (br d, 1H), 6.95 (s, 1H). Mass spectrum:(M+H)⁺=354.

F.N-((N-Methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 58E provided 0.64 g(87%) of the desired compound.

G.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1%methanol in chloroform, 50 mg (36%) of the desired compound (R_(f) 0.40,5% methanol in chloroform) as a solid, mp 70-71° C. Mass spectrum:(M+H)⁺=747. Anal. Calcd for C₃₉H₅₀N₆O₅S₂: C, 62.71; H, 6.75; N, 11.25.Found: C, 63.16; H, 6.80; N, 10.84.

EXAMPLE 59 A. 3-Methylbutanamide

Using the procedure of Example 44A but replacing 2-ethylbutyric acidwith 3-methylbutyric acid provided 4.2 g (100%) of the crude desiredcompound.

B. 3-Methylpropanethiocarboxamide

Using the procedure of Example 1O, but replacing isobutyramide with3-methylbutanamide provided the crude desired compound.

C. (4-(Chloromethyl)-2-isobutylthiazole Hydrochloride

Using the procedure of Example 1P, but replacing2-methylpropanethioamide with 3-Methylpropanethiocarboxamide providedthe crude desired compound as a yellow oil.

D. (2-Isobutyl-4-(((N-methyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-isobutylthiazole hydrochloride provided, afterpurification of the residue by silica gel chromatography using 10%methanol in chloroform, 0.61 g (31%) of the desired compound.

E.N-((N-Methyl-N-((2-isobutyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isobutyl-4-(((N-methyl)amino)methyl)thiazole provided, afterpurification by silica gel chromatography using 1% methanon inchloroform as an eluent, 0.40 g (32%) of the desired compound. Massspectrum: (M+H)⁺342.

F.N-((N-Methyl-N-((2-isobutyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 59E provided 0.13 g(70%) of the desired compound.

G.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isobutyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-((2-isobutyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1%methanol in chloroform, 50 mg (33%) of the desired compound (R_(f) 0.65,10% methanol in chloroform). Mass spectrum: (M+H)⁺=735.

EXAMPLE 60 A. (2-Cyclopentyl-4-(((N-ethyl)amino)methyl)thiazole

Using the procedure of Example 1Q, but replacing4-(chloromethyl)-2-isopropylthiazole hydrochloride with4-(chloromethyl)-2-cyclopentylthiazole hydrochloride and replacing 40%aqueous methylamine with 70% aqueous ethylamine provided, afterpurification of the residue by silica gel chromatography using 5%methanol in chloroform, 1.08 g (50%) of the desired compound.

B.N-((N-Ethyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-cyclopentyl-4-(((N-ethyl)amino)methyl)-thiazole provided, afterpurification by silica gel chromatography using 1% methanol inchloroform as an eluent, 0.40 g (46%) of the desired compound. ¹¹H NMR(DMSO-d₆) δ 1.00 (t, J=7 Hz, 3H), 1.29 (d, J=7 Hz, 3H), 1.6-1.8 (m, 9H),2.1 (m, 3H), 3.27 (m, 2H), 3H), (m, 1H), 3.60 (s, 3H), 4.17 (pentet, J=7Hz, 1H), 4.41 (AA′, 2H), 6.80 (d, J=7 Hz, 1H), 7.20 (s, 1H). Massspectrum: (M+H)⁺=340.

C.N-((N-Ethyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 60B provided 0.13 g(69%) of the desired compound.

D.(2S,3S,5S)-5-(N-(N-((N-Ethyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-ethyl-N-((2-cyclopentyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1.5%methanol in chloroform, 50 mg (34%) of the desired compound (R_(f) 0.63,10% methanol in chloroform) as a solid, mp 67-69° C. Mass spectrum:(M+H)⁺=733. Anal. Calcd for C₃₈H₄₈N₆O₅S₂: C, 62.27; H, 6.60; N, 11.47.Found: C, 62.02; H, 6.74; N, 10.98.

EXAMPLE 61 A. (2-Isopropyl-4-(2-((N-methyl)amino)ethyl)thiazole

A solution of 2.0 g (12 mmol) of 2-isopropyl-4-(hydroxyethyl)thiazole in50 ml of tetrahydrofuran was treated with 1.34 g (12 mmol) ofmethanesulfonyl chloride. The resulting solution was treated dropwisewith 3.4 ml (24 mmol) of triethylamine and stirred at ambienttemperature for 1 h. A portion (25 ml) of the resulting solution wasadded to 50 ml of aqueous ethylamine (70% in H₂O) with rapid stirring.After addition, the mixture was heated to reflux for 2 h, allowed tocool, diluted with ethyl acetate, washed with aqueous NaHCO₃ andsaturated brine, dried over Na₂SO₄, and concentrated in vacuo to providethe crude desired compound. Purification of the residue by silica gelchromatography using 5% methanol in chloroform, 0.52 g (48%) of thedesired compound. ¹H NMR (CDCl₃) δ 1.38 (d, J=7 Hz, 3H), 2.46 (s, 3H),2.93 (s, 4H), 3.30 (heptet, J=7 Hz, 1H), 6.79 (s, 1H). Mass spectrum:(M+H)⁺=185.

B.N-((N-Methyl-N-(2-(2-isopropyl-4-thiazolyl)ethyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isopropyl-4-(2-((N-methyl)amino)ethyl)-thiazole provided, afterpurification by silica gel chromatography using 1% methanol inchloroform as an eluent, 0.16 g (35%) of the desired compound. ¹¹H NMR(CDCl₃) δ 0.91 (d, J=7 Hz, 3H), 0.98 (d, J=7 Hz, 3H), 1.48 (d, J=7 Hz,3H), 1.49 (d, J=7 Hz, 3H), 2.11 (heptet of doublets, J=7, 5 Hz, 1H),2.85 (s, 3H), 2.99 (t, J=7 Hz, 2H), 3.30 (heptet, J=7 Hz, 1H), 3.63 (t,J=7 Hz, 2H), 3.73 (s, 3H), 4.42 (dd, J=8, 5 Hz, 1H), 4.93 (br d, J=8 Hz,1H), 6.83 (s, 1H). Mass spectrum: (M+H)⁺=342.

C.N-((N-Methyl-N-(2-(2-isopropyl-4-thiazolyl)ethyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 61B provided 0.074g (64%) of the desired compound.

D.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-(2-(2-isopropyl-4-thiazolyl)ethyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U, but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-methyl-N-(2-(2-isopropyl-4-thiazolyl)ethyl)amino)carbonyl)-L-valineprovided, after purification by silica gel chromatography using 1%methanol in chloroform, 90 mg (54%) of the desired compound (R_(f) 0.44,10% methanol in chloroform) as a solid, mp 62-63° C. Mass spectrum:(M+H)⁺=735. Anal. Calcd for C₃₈H₅₀N₆O₅S₂: C, 62.10; H, 6.86; N, 11.43;S, 8.72. Found: C, 61.72; H, 6.78; N, 11.34; S, 8.89.

EXAMPLE 62 A.(2-Isopropyl-4-((N-(tert-butyloxycarbonylamino)amino)methyl)thiazole

A solution of 7.5 g (57 mmol) to t-butylcarbazate in 200 ml of isopropylalcohol was treated with a solution of 1.0 g (57 mmol) of4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of isopropylalcohol. The resulting solution was heated at reflux for 16 h, allowedto cool, and concentrated in vacuo. The residue was diluted with 1N HCl,washed with three portions of ethyl acetate, basified to pH 12 withaqueous NaOH, and extracted with three portion of ethyl acetate. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.Purification of the residue by silica gel chromatography using 20% ethylacetate in hexane provided 0.32 g (21%) of the desired compound (R_(f)0.4, 5% methanol in chloroform). ¹H NMR (CDCl₃) δ 1.40 (d, J=7 Hz, 6H),1.47 (s, 9H), 2.53 (br, 1H), 3.33 (heptet, J=7 Hz, 1H), 4.11 (s, 2H),6.22 (br, 1H), 7.01 (s, 1H). Mass spectrum: (M+H)⁺=272.

B.N-((N-(tert-Butyloxycarbonylamino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Using the procedure of Example 1S, but replacing2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with2-isopropyl-4-((N-(tert-butyloxycarbonylamino)amino)methyl)thiazoleprovided, after silica gel chromatography using 1% methanol inchloroform as an eluent, 0.30 g (95%) of the desired compound. ¹H NMR(DMSO-d₆) δ 0.84 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 1.31 (d, J=7 Hz,6H), 1.39 (s, 9H), 2.05 (m, 1H), 3.24 (m, 1H), 3.64 (s, 3H), 4.09 (dd,J=9, 6 Hz, 1H), 6.35 (br, 1H), 7.24 (s, 1H). Mass spectrum: (M+H)⁺=429.

C.N-((N-(tert-Butyloxycarbonylamino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

Using the procedure of Example 1T, but replacing the resultant compoundof Example 1S with the resultant compound of Example 62B provided thedesired compound.

D.(2S,3S,5S)-5-(N-(N-((N-(tert-Butyloxycarbonylamino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewithN-((N-(tert-butyloxycarbonylamino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineprovided, after silica gel chromatography using 1% methanol inchloroform, 80 mg (41%) of the desired compound (R_(f) 0.35, 5% methanolin chloroform). Mass spectrum: (M+H)⁺=822. HRMS, Exact mass calcd forC₄₁H₅₆N₇O₇S₂: 822.3683. Found: 822.3682.

EXAMPLE 63(2S,3S,5S)-5-(N-(N-((N-(Amino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneHydrochloride

To 60 mg (0.073 mmol) of(2S,3S,5S)-5-(N-(N-((N-(tert-butyloxycarbonyl-amino)-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewas added 5 ml of 4 M HCl in dioxane. The resulting solution was stirredat ambient temperature for 2 h. After concentration of the solution invacuo, the residue was taken up in 0.5 ml of methanol, added to 20 ml ofdiethyl ether, and filtered to provide 40 mg (77%) of the desiredcompound (R_(f) 0.60, 10% methanol in chloroform). Mass spectrum:(M+H)⁺=722.

EXAMPLE 64(2S,3S,5S)-5-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane

Using the procedure of Example 1U but replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexaneand replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine provided, aftersilica gel chromatography using 10% methanol in dichloromethane, 25 mg(76%) of the desired compound (R_(f) 0.47, 10% methanol indichloromethane). Mass spectrum: (M+H)⁺=715.

EXAMPLE 65 A.(2S,3S,5S)-3-(tert-Butyldimethylsilyloxy)-2-(tert-butyloxycarbonylamino)-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)hexane

Using the procedure of Example 8F, but replacing benzyl alcohol with5-(hydroxymethyl)thiazole provided, after silica gel chromatographyusing 10% methanol in dichloromethane, 261 mg (67%) of the desiredcompound. ¹H NMR (CDCl₃) δ 0.05 (s, 6H), 0.91 (s, 9H), 1.34 (s, 9H),1.70 (m, 2H), 2.72 (m, 2H), 3.03 (m, 2H), 3.74 (m, 1H), 3.91 (m, 1H),4.02 (m, 1H), 4.63 (br d, 1H), 5.24 (s, 2H), 7.19-7.35 (m, 5H), 7.52 (s,1H), 7.86 (s, 1H), 8.66 (s, 1H), 8.79 (s, 1H). Mass spectrum:(M+H)⁺=647.

B.(2S,3S,5S)-2-(tert-Butyloxycarbonylamino)-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane

Using the procedure of Example 8G, but replacing the resultant compoundof Example 8F with the resultant compound of Example 65A provided; aftersilica gel chromatography using 10% methanol in dichloromethane, 74 mg(35%) of the desired compound. ¹H NMR (CDCl₃) δ 1.39 (s, 9H), 1.65 (m,2H), 2.87 (m, 2H), 3.09 (m, 2H), 3.68 (m, 2H), 3.96 (m, 2H), 4.74 (br d,1H), 5.26 (dd, 2H), 7.17-7.32 (m, 5H), 7.52 (s, 1H), 7.86 (s, 1H), 8.66(s, 1H), 8.81 (s, 1H). Mass spectrum: (M+H)⁺=533;

C.(2S,3S,5S)-2-Amino-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane

A solution of 70 mg (0.13 mmol) of the resultant compound of Example 65Bin 2.1 ml of CH₂Cl₂ was treated with 0.7 ml of trifluoroacetic acid,stirred for 1.5 h, and concentrated in vacuo. The residue was treatedwith 3 ml of aqueous NaHCO₃, extracted with three portions of 95:5CH₂Cl₂:CHCl₃, dried over Na₂SO₄, and concentrated in vacuo to provide 55mg (97%) of the desired compound as a white foamy solid. ¹H NMR (CDCl₃)δ 1.72 (m, 2H), 1.86 (br, 2H), 2.46 (dd, 1H), 2.84 (m, 2H), 3.20 (m,2H), 3.45 (m, 1H), 4.02 (m, 1H), 5.30 (dd, 2H), 5.52 (br d, 1H),7.14-7.34 (m, 5H), 7.59 (s, 1H), 7.88 (s, 1H), 8.67 (s, 1H), 8.80 (s,1H). Mass spectrum: (M+H)⁺=433.

D.(2S,3S,5S)-2-(N-(N-((2-Isopropyl-4-thiazolyl)methoxycarbonyl)valinyl)amino)-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane

Using the procedure of Example 1U but replacingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinewith N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine and replacing(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexaneprovided, after silica gel chromatography using 1% methanol inchloroform, 54 mg (66%) of the desired compound (R_(f) 0.6, 10% methanolin CH₂Cl₂).

¹H NMR (DMSO-d₆) δ 0.69 (d, 3H), 0.74 (d, 3H), 1.31 (d, 6H), 1.47 (m,2H), 1.85 (m, 1H), 2.75 (m, 4H), 2.95 (m, 1H), 3.57 (m, 1H), 3.80 (m,2H), 4.08 (m, 1H), 4.95 (d, 1H), 5.03 (s, 2H), 5.19 (s, 2H), 7.12-7.29(m), 7.45 (s, 1H), 7.47 (s, 1H). Mass spectrum: (M+H)⁺=715.

EXAMPLE 66 (2S, 3S, 5S)-2,5-Diamino-3-hydroxy-1,6-diphenylhexaneDihydrochloride EXAMPLE 66A

(L)-N,N-Dibenzylphenylalanine Benzyl Ester

A solution containing L-phenylalanine (11 kg, 66.7 moles), potassiumcarbonate (29 kg, 210 moles), and water (66 L), and benzyl chloride (27kg; 213 moles) was heated to 90±15° C. for 10-24 hours. The reactionmixture was cooled to room temperature and heptane (29 L) and tap water(27 L) was added. The layers were separated and the organics washed oneto two times with 22 L of a methanol/water solution (1/2 v/v). Theorganics were then stripped to give the desired product as an oil. IR(neat) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm⁻¹, ¹H NMR (300 MHz,CDCl₃) δ 7.5-7.0 (m, 20H), 5.3 (d, 1H, J=13.5 Hz), 5.2 (d, 1H, J=13.5Hz), 4.0 (d, 2H, J=15 Hz), 3.8 (t, 2H, J=8.4 Hz), 3.6 (d, 2H, J=15 Hz),3.2 (dd, 1H, J=8.4, 14.4 Hz), ¹³C NMR (300 MHz, CDCl₃) δ 172.0, 139.2,138.0, 135.9, 129.4, 128.6, 128.5, 128.4, 128.2, 128.1, 128.1, 126.9,126.2, 66.0, 62.3, 54.3, 35.6. [α]_(D) −79° (c=0.9, DMF).

EXAMPLE 66B (4S)-4-(N,N-Dibenzylamino)-3-oxo-5-phenyl-pentanonitrile

A solution containing the product of Example 66A (i.e., benzyl ester)(approx. 0.45 moles) in 520 mL tetrahydrofuran and 420 mL acetonitrilewas cooled to −40° C. under nitrogen. A second solution containingsodium amide (48.7 g, 1.25 moles) in 850 mL tetrahydrofuran was cooledto −40° C. To the sodium amide solution was slowly added 75 mLacetonitrile and the resulting solution was stirred at −40° C. for morethan 15 minutes. The sodium amide/acetonitrile solution was then slowlyadded to the benzyl ester solution at −40° C. The combined solution wasstirred at −40° C. for one hour and then quenched with 1150 mL of a 25%(w/v) citric acid solution. The resulting slurry was warmed to ambienttemperature and the organics separated. The organics were then washedwith 350 mL of a 25% (w/v) sodium chloride solution, then diluted with900 mL heptane. The organics were then washed three times with 900 mL ofa 5% (w/v) sodium chloride solution, two times with 900 mL of a 10%methanolic water solution, one time with 900 mL of a 15% methanolicwater solution, and then one time with 900 mL of a 20% methanolic watersolution. The organic solvent was removed in vacuo and the resultingmaterial dissolved into 700 mL of hot ethanol. Upon cooling to roomtemperature, the desired product precipitated. Filtration gave thedesired product in 59% yield from the L-phenylalanine. IR (CHCl₃) 3090,3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 1300, 1215 cm⁻¹, ¹H NMR(CDCl₃) δ 7.3 (m, 15H), 3.9 (d, 1H, J=19.5 Hz), 3.8 (d, 2H, J=13.5 Hz),3.6 (d, 2H, J=13.5 Hz), 3.5 (dd, 1H, J=4.0, 10.5 Hz), 3.2 (dd, 1H,J=10.5, 13.5 Hz), 3.0 (dd, 1H, J=4.0, 13.5 Hz), 3.0 (d, 1H, J=19.5 Hz),¹³C NMR (300 MHz, CDCl₃) δ 197.0, 138.4, 138.0, 129.5, 129.0, 128.8,128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4. [α]_(D) −95° (c=0.5, DMF).

EXAMPLE 66C Alternate Preparation of(4S)-4-(N,N-Dibenzylamino)-3-oxo-5-phenylpentanonitrile

To a flask was charged sodium amide (5.8 g, 134 mmol) under nitrogenfollowed by 100 mL of methyl t-butyl ether (MTBE). The stirred solutionwas cooled to 0° C. Acetonitrile (8.6 mL, 165 mmol) was added over 1minute. This solution was stirred at 5±5° C. for 30 minutes. A solutionof (L)-N,N-dibenzylphenylalanine benzyl ester (25 g, 90% pure, 51.6mmol) in 125 mL of MTBE was added over 15 minutes and the resultingheterogeneous mixture was stirred at 5±5° C. until the reaction wascomplete (approx. 3 hours). The reaction was quenched with 100 mL of 25%w/v aqueous citric acid and warmed to 25° C. before separating thelayers. The organics were then washed with 100 mL of H₂O. The aqueouslayer was separated and the organics filtered and concentrated in vacuo.The residue was crystallized from 50 mL of ethanol to afford 13.8 g ofthe desired product as a white solid.

EXAMPLE 66D(5S)-2-Amino-5-(N,N-dibenzylamino)-4-oxo-1,6-diphenylhex-2-ene

To a 5° C. solution of the product of Example 66B (20 Kg, 29 moles) in29 L tetrahydrofuran was added benzylmagnesium chloride (45 Kg, 2M inTHF, 84.5 moles). The solution was warmed to ambient temperature andstirred until analysis showed no starting material. The solution wasthen recooled to 5° C. and 54 L of a 15% citric acid solution was slowlyadded to quench excess benzylmagnesium chloride. The organics wereseparated and washed with 27 L 10% sodium chloride and stripped to asolid. The product was stripped again from 27 L ethanol (200 proof) andthen dissolved in 67 L hot ethanol (200 proof). After cooling to roomtemperature and stirring for 12 hours, the resulting product wasfiltered and dried in a vacuum oven at 30° C. to give 24 kg of thedesired product. mp 101-1 02° C., IR (CDCl₃) 3630, 3500, 3110, 3060,3030, 2230, 1620, 1595, 1520, 1495, 1450 cm⁻¹, ¹H NMR (300 MHZ, CDCl₃) d9.8 (br s, 1H), 7.2 (m, 20H), 5.1 (s, 1H), 4.9 (br s, 1H), 3.8 (d, 2H,J=14.7 Hz), 3.6 (d, 2H, J=14.7 Hz), 3.5 (m, 3H), 3.2 (dd, 1H, J=7.5,14.4 Hz), 3.0 (dd, 1H, J=6.6, 14.4 Hz), ¹³C NMR (CDCl₃) d 198.0, 162.8,140.2, 140.1, 136.0, 129.5, 129.3, 128.9, 128.7, 128.1, 128.0, 127.3,126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4. [α]_(D)−147° (c=0.5, DMF).

EXAMPLE 66E(2S,3S,5S)-5-Amino-2-(N,N-dibenzylamino)-3-hydroxy-1,6-diphenylhexane

(i). A suspension of sodium borohydride (6.6 kg, 175 moles) intetrahydrofuran (157 L) was cooled to less than −10±5° C.Methanesulfonic acid (41.6 kg, 433 moles) was slowly added and thetemperature kept below 0° C. during the addition. Once the addition wascomplete, a solution of water (6 L, 333 moles), the product of Example66D (20 kg, 43 moles) and tetrahydrofuran (61 L) was slowly added whilemaintaining the temperature below 0° C. during the addition. The mixturewas stirred for not less than 19 h at 0±5° C.

(ii). To a separate flask was added sodium borohydride (6.6 kg, 175moles) and tetrahydrofuran (157 L). After cooling to −5±5° C.,trifluoroacetic acid (24.8 kg, 218 moles) was added while maintainingthe temperature below −15° C. The solution was stirred 30 min at 15±5°C. and was then added to the reaction mixture resulting from step (i),keeping the temperature at less than 20° C. This was stirred at 20±5° C.until reaction was complete. The solution was then cooled to 10±5° C.and quenched with 3N NaOH (195 kg). After agitating with tert-butylmethyl ether (162 L), the organic layer was separated and washed onetime with 0.5N NaOH (200 kg), one time with 20% w/v aqueous ammoniumchloride (195 kg), and two times with 25% aqueous sodium chloride (160kg). The organics were stripped to give the desired product as an oilwhich was used directly in the next step.

IR (CHCl₃) 3510, 3400, 3110, 3060, 3030, 1630, ¹H NMR (300 MHz, CDCl₃) δ7.2 (m, 20H), 4.1 (d, 2H, J=13.5 Hz), 3.65 (m, 1H), 3.5 (d, 2H, J=13.5Hz), 3.1 (m, 2H), 2.8 (m, 1H), 2.65 (m, 3H), 1.55 (m, 1H), 1.30 (m, 1H),¹³C NMR (300 MHz, CDCl₃) δ 140.8, 140.1, 138.2, 129.4, 129.4, 128.6,128.4, 128.3, 128.2, 126.8, 126.3, 125.7, 72.0, 63.6, 54.9, 53.3, 46.2,40.1, 30.2.

EXAMPLE 66F (2S,3S,5S)-2,5-Diamino-3-hydroxy-1,6-diphenylhexaneDihydrochloride

To a stirred solution of[2S,3S,5S]-2-(N,N-dibenzylamino)-3-hydroxy-5-amino-1,6-diphenylhexane(20 kg, 43.1 mol) in methanol (250 kg) was added an aqueous solution ofammonium formate (13.6 kg, 215 mol) in water (23 kg) and an aqueoussuspension of 5% wet palladium on carbon (4.0 kg, Degussa catalyst, E101NE/W, approximately 50-60% water by weight). The suspension whichresulted was heated to reflux (70±10° C.) for 6 hours and then cooled toroom temperature. The suspension was filtered through a bed ofdiatomaceous earth and the cake was washed with methanol (2×30 kg). Thefiltrate was concentrated via vacuum distillation to an aqueous oil. Theaqueous residue was taken up in 1N NaOH (200 liters) and extracted withethyl acetate (155 kg). The organic product layer was washed with a 20%aqueous sodium chloride solution (194 kg) and then with water (97 kg).The ethyl acetate product solution was then concentrated to an oil undervacuum distillation. Isopropanol (40 kg) was then charged to the residueand again the solution was concentrated to an oil with vacuumdistillation. To the oil was charged isopropanol (160 kg) andconcentrated aqueous hydrochloric acid (20.0 kg). Thesuspension/solution was then heated to reflux for 1 hour and then slowlycooled to room temperature. The slurry was then stirred for 12-16 hours.The slurry was filtered and the cake was washed with ethyl acetate (30kg). The wet cake was resuspended in isopropanol (93 kg) and water (6.25kg) and heated to reflux for 1 hour with stirring. The reaction mixturewas then slowly cooled to room temperature and stirred for 12-16 hours.The reaction mixture was filtered and the wet cake was washed withisopropanol (12 kg). The solid was dried in a vacuum oven at 45° C. forapproximately 24 hours to provide 7.5 kg of the desired product. ¹H NMR(300 MHz, CD₃OD) δ 7.40-7.15 (m, 1OH), 3.8 (ddd, 1H, J=11.4, 3.7, 3.7Hz), 3.68-3.58 (m, 1H), 3.37 (ddd, 1H, J=7.5, 7.5, 3.5 Hz), 3.05-2.80(m, 4H), 1.95-1.70 (m, 2H), ¹³C NMR (300 MHz, CD₃OD) δ 135.3, 135.1,129.0, 128.9, 128.7, 128.7, 127.12, 127.07, 67.4, 57.1, 51.6, 38.4,35.5, 35.2.

EXAMPLE 67(2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexaneEXAMPLE 67A(2S,3S,5S)-2-(N,N-dibenzylamino)-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

To a stirred solution of(2S,3S,5S)-2-(N,N-dibenzylamino)-3-hydroxy-5-amino-1,6-diphenylhexane(10.0 g, 21.6 mmol) in tetrahydrofuran (200 mL) was added potasiumcarbonate (6.0 g, 43.2 mmol) in H₂O (200 mL). To this solution was addeddi-t-butyldicarbonate (5.64 g, 25.9 mmol) in tetrahydrofuran (10 mL).The solution which resulted was stirred at room temperature for 3 hours.N,N-dimethylethylenediamine (1 mL, 8.6 mmol) was added and the reactionmixture was stirred at room temperature for an additional hour. Ethylacetate (400 mL) was added and the organic layer was separated andwashed with 5% KH₂PO₄ (2×200 mL), water (1×200 mL), saturated NaHCO₃(2×200 mL) and water (1×200 mL). The organic solution was then driedover sodium sulfate and concentrated under reduced pressure to providethe desired product as a light yellow oil. 300 MHz ¹H NMR (CDCl₃) δ 1.40(s, 9H), 1.58 (s, 2H), 2.45-2.85 (m, 4H), 3.05 (m, 1H), 3.38 (d, 2H),3.6 (m, 1H), 3.79 (m, 1H), 3.87 (d, 2H), 4.35 (s, 1H), 4.85 (s, broad,1H), 7.0-7.38 (m, 20H).

EXAMPLE 67B(2S,3S,5S)-2-amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

To a stirred solution of(2S,3S,5S)-2-(N,N-dibenzylamino)-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane(12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate(8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). Thesolution was stirred under nitrogen at 60° C. for three hours and thenat 75° C. for 12 hours. An additional amount of ammonium formate (6 g)and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacialacetic acid. The reaction was driven to completion within 2 hours at areflux temperature. The reaction mixture was then cooled to roomtemperature and then filtered through a bed of celite. The filter cakewas washed with methanol (75 mL) and the combined filtrates wereconcentrated under reduced pressure. The residue was taken up in 1N NaOH(300 mL) and extracted into methylene chloride (2×200 mL). The combinedorganic layers were washed with brine (250 mL) and dried over sodiumsulfate. Concentration of the solution under reduced pressure providedthe desired product as a light colored oil which slowly crystallizedupon standing (5 g). Further purification of the product could beaccomplished by flash chromatography (silica gel, 5% methanol inmethylene chloride). 300 MHz ¹H NMR (CDCl₃) δ 1.42 (s, 9H), 1.58 (m,1H), 1.70 (m, 1H), 2.20 (s, broad, 2H), 2.52 (m, 11H), 2.76-2.95 (m,4H), −3.50 (m, 1H), 3.95 (m, 1H), 4.80 (d, broad, 1H), 7.15-7.30 (m,10H).

EXAMPLE 68 Alternative Preparation of(2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexaneEXAMPLE 68A(5S)-2-(t-Butyloxycarbonylamino)-5-(N,N-dibenzylamino)-1,6-diphenyl-4-oxo-2-hexene

To 9.21 gm (20 mmol) of the resultant compound of Example 66D and 0.37gm (3 mmol) 4-N,N-dimethylaminopyridine in 100 ml of methyltert-butylether was added via syringe pump a solution containing 4.80 gm(22 mmol) di-tert-butyl dicarbonate in the same solvent (25 ml) over aperiod of 6 h. An additional amount (3 ml) of methyl tert-butylether wasthen added to complete the addition. After stirring at room temperaturefor 18 h the reaction mixture was cooled with the aid of an ice waterbath. The resultant solid was collected by suction filtration and washedwith cold (0° C.) methyl tert-butylether and hexane and dried undervacuum to give 9.9 gm of crude material as a white solid. The materialthus isolated was disolved in a minimal amount of dichloromethane andpurified by flash chromatography on silica gel. Elution of the columnwith a mixture of hexane-ethyl acetatedichloromethane (8:1:1) gave,after concentration of the appropriate fractions, 8.1 gm (72%) of thedesired compound. Mp. 191-193° C. [α]_(D) −183.7° (c=1.05, CHCl₃). ¹HNMR (CDCl₃, δ): 11.68 (bs, 1H), 7.05-7.47 (m, 20H), 5.28 (s, 1H), 4.27(d, J=16 Hz, 1H), 4.02 (d, J=16 Hz, 1H), 3.58 (m, 4H), 3.40 (m, 1H),3.11 (m, 1H), 2.90 (m, 1H), 1.48 (s, 9H).

EXAMPLE 68B Alternate Preparation of(5S)-2-(t-Butyloxycarbonylamino)-5-(N,N-dibenzylamino)-1,6-diphenyl-4-oxo-2-hexene

A suspension of(S)-2-amino-5-(N,N-dibenzylamino)-1,6-diphenyl-4-oxo-2-hexene (100.0 g,0.217 mol) in 15% ethyl acetate/hexanes (2 liters) under N₂ was warmedto about 40° C. The resulting solution was cooled to room temperaturebefore adding 4.0 g (33 mmol) of N,N-dimethyl-4-aminopyridine and 49.7 g(0.228 mol) of di-tert-butyl dicarbonate. The reaction mixture wasallowed to stir overnight at room temperature. (After approximately onehour, a white precipitate began to form.) The suspension was filteredand the precipitate was washed with hexanes to afford the desiredproduct as colorless crystals. TLC: 25% ethyl acetate/hexanes R_(f)0.38.

EXAMPLE 68C(2S,3S,5S)-2-(N,N-Dibenzylamino)-5-(t-butyloxycarbonylamino)-3-hydroxy-1,6-diphenylhexane

A solution of the product of Example 68A (5 g, 8.9 mmol) indichloromethane (100 ml) and 1,4-dioxolane (100 ml) was cooled tobetween −10° and −15° C. and treated dropwise with 1M BH₃THF (26.7 ml,26.7 mmol). The solution was stirred at this temperature for 3 hr. Theclear solution was quenched with excess methanol (20 ml) and stirred atroom temperature for 30 min. The solvent was removed in vacuo.

The resulting white foam was dissolved in THF (75 ml) and cooled to −40°C. A solution of LAH (9 ml, 1M in THF, 9 mmol) was added dropwise. After10 min. the solution was quenched with water followed by dilute aqueousHCl. The organics were removed and the aqueous layer extracted withethyl acetate (3×20 ml). The combined organics were washed (saturatedaqueous bicarbonate followed by brine), dried (Na₂SO₄), filtered andevaporated to afford 4.9 g (99%) of the desired product as a white foam.

Alternatively, the white foam resulting from the BH₃THF reaction stepwas dissolved in MeOH (45 ml), cooled to +3° C. and treated portionwisewith KBH4 (1.44 g, 26.7 mmol). After addition of the last portion ofKBH₄ the reaction was stirred for an additional 4 hours at +4 to +5° C.The solution was concentrated by 1/2 the volume in vacuo, diluted with1/1 hexane-EtOAc (70 ml) and quenched (with cooling, maintain temp. <30°C.) by adding a 10% solution of KHSO₄ to pH=about 5. NaOH (15% aqueous)was added to pH=12-13. The insoluble salts were removed by filtration,and the filter cake washed 3 times with 7 ml 1/1 hexane/EtOAc. Thefiltrate and washes were transferred to a separatory funnel, dilutedwith 15 ml hexane and 15 ml H₂O. The organics were removed and theaqueous layer was extracted once with 20 ml (1/1) hexane-EtOAc. Thecombined organics were washed (saturated brine), dried (Na₂SO₄),filtered, and evaporated to afford 5.2 g of the desired product whichwas used without further purification in subsequent reactions.

R_(f) 0.5 (25% EtOAc/hexane) ¹H NMR (CDCl₃) δ 7.37-7.10 (m 20H); 6.78(br. s, 1H); 4.62 (d, 1H); 4.50 (s, 1H); 4.18 (dd, 1H); 3.9 (d, 2H);3.65 (dd, 2H); 3.40 (d, 2H); 3.00 (m, 2H); 2.77 (m, 1H); 1.39 (s, 9H).MS (EI) m/e565 (M+H).

EXAMPLE 68D(2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

A solution of the product from Example 68C (150 gm, 250 mmol) dissolvedin absolute EtOH (2 liters) was treated with 10% Pd/C (18 gm,pre-wetted), followed by addition of ammonium formate (78.6 gms, 1.25moles) dissolved in H₂O (200 ml). The resulting mixture was stirred atreflux for 2.5 hours. The mixture was cooled to room temperature andfiltered through a pad of infusorial earth (20 g). The filter cake waswashed 3 times with EtOH (70 ml each). The filtrate was concentrated invacuo. The residue was dissolved into EtOAc (1 L) and washed (1N NaOH,followed by H₂O, followed by brine), dried (Na₂SO₄), filtered andconcentrated in vacuo. to a constant weight of 95 gms. (99.2% oftheory). The light yellow solid (91.5 gm of the 95 gm) was slurried inhot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml),and swirled to effect solution. The solution was allowed to slowly coolto room temperature over 3 hours, kept at room temperature for 2 morehours and filtered. The filter cake was washed 10 times with 9/1hexane-isopropanol (30 ml each) to give the desired product as anoff-white finely crystalline solid which was dried to constant weight of57.5 gm.

The crude product (20 gm) was recrystallized from hot 140 ml heptane/17ml isopropanol. After letting the solution cool slowly to roomtemperature, the mixture was let stand at room temperature for 2 hoursand then filtered. The filter cake was rinsed (5×15 ml (8/1)heptane/isopropanol) and dried to a constant weight of 18.5 gm.

EXAMPLE 69 Alternative Preparation of(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneEXAMPLE 69A(2S,3S,5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

The product of Example 68D (6.0 g, 15.6 mmoles) was dissolved in 60 mLof DMF under nitrogen atmosphere. To this stirred solution at roomtemperature was added 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole(4.67 g, 15.6 mmole) and the resulting solution was stirred for 4 h. Thesolvent was removed under reduced pressure by rotary evaporation and theresidue dissolved in 150 mL EtOAc. This solution was washed with 5×75 mL1N NaOH solution, 100 mL brine, dried over Na₂SO₄. The solvent wasremoved to afford 8.02 g of a slightly yellowish oil. This material wascrystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) ofthe desired product as a white solid. mp 118-120° C. H,¹NMR (CDCl₃) δ8.79 (s, 1H), 7.83 (s, 1H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s,2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m,1H), 2.85 (d-apparent, 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz),1.61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)⁺, 543 (M+18)⁺.

EXAMPLE 69B(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

The product of Example 69A (6.43 g, 12.23 mmoles) was dissolved in 25 mLdioxane at room temperature under nitrogen atmosphere. To this stirredsolution was added 20.25 mL of 4N HCl in dioxane, and afterapproximately 10 min a thick precipitate formed. An additional 10 mL ofdioxane was added to loosen up the slurry. This mixture was stirred for1 h and then filtered. The filter cake of the product bis-HCl salt waswashed with 20 mL dioxane, air dried, and then dissolved in 175 mLwater. To this solution was added 175 mL ethyl acetate and the two phasemixture rapidly stirred. The pH of this mixture was adjusted to pH=10 bythe dropwise addition of 3N NaOH to the rapidly stirred mixture. Theorganic layer was isolated, washed with brine (150 mL), and dried overNa₂SO₄. The solvent was removed to afford 5.18 g (99%) of the desiredproduct as a clear oil. H¹ NMR (CDCl₃) δ 8.81 (s, 1H), 7.87 (s, 1H),7.35-7.05 (m, 10H), 5.33 (d, 1H, J=9.3 Hz), 5.28 (m,2H), 3.81 (m, 1H),3.72 (m, 1H), 3.01 (m, 1H), 2.88 (m, 2H), 2.78 (dd, 1H, J=13.5, 5.1 Hz),2.39 (dd, 1H, J=9.0, 4.5 Hz), 1.57-1.30 (m, 2H). CIMS m/z 426 (M+H)⁺.

EXAMPLE 69C(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine(4.13 g, 13.18 mmole) and hydroxybenztriazole (2.23 g, 16.48 mmoles)were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g,13.18 mmoles) was added in one portion to the stirred solution undernitrogen atmosphere. This mixture was stirred for 4 h at roomtemperature and then filtered to remove dicyclohexylurea precipitate.The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mLTHF under nitrogen atmosphere. To this stirred solution was added thefiltrate of HOBT-active ester and the resulting solution was stirred atroom temperature for 4 h, and the solvent removed via rotaryevaporation. The residue was dissolved in 150 mL ethyl acetate andwashed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueousKHSO₄ and the solvent was removed by rotary evaporation to afford aresidue. The residue was dissolved in 175 mL 1N HCL, and the solutionfiltered to remove the small quantity of dicyclohexylurea. The filtratesolution was added to 175 mL ethyl acetate and the two phase mixturerapidly mixed. The pH of this rapidly stirred mixture was adjusted topH=7 by dropwise addition of cold 3N NaOH. The organic layer wasisolated, washed with 100 mL brine, dried over Na₂SO₄, filtered, and thesolvent was removed to afford 8.6 g of a colorless foam. This materialwas crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of thedesired product as a white solid. mp=122-123° C. CIMS m/z 721 (M+H)⁺.

EXAMPLE 70 Alternative Preparation of(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Alternative A

The product of Example 66F (9.5 g, 33.4 mmol) and phenylboronic acid(4.1 g, 33.6 mmol) were combined in toluene (150 mL) and refluxed for2.5 hours with azeotropic water removal (Dean-Stark trap). Toluene (100mL) was distilled out at atmospheric pressure, then the remainingtoluene was removed under vacuum, to provide a yellow syrup which wasdissolved in DMF (50 mL) and cooled to −60° C. A solution of5-(p-nitrophenyloxycarbonyloxy-methyl)thiazole (9.5 g, 33.5 mmol) in DMF(50 mL) was added over 45 minutes. The resulting mixture was stirred for8 hours at −55±5°C., then 14 hours at −25° C., then was allowed to warmto room temperature. The reaction mixture was diluted with 1N HCl (250mL) and washed with CH₂Cl₂ (2×80 mL). The combined organic layers wereback-extracted with 1N HCl (60 mL). The combined aqueous HCl layers werecooled in an ice-bath to 2° C., and conc. (37%) HCL (30 mL) was addedover 5 minutes. The desired product (bis HCl salt) began to precipitatewithin 30 minutes. The slurry was stirred 3 hours at 2-5° C., then theproduct (bis HCl salt) was collected by filtration and dried in a vacuumoven at 55-60° C. Yield 11.4 g (68%).

Second Crop Recovery:

The HCl mother liquors were stirred With ethyl acetate (190 mL) andneutralized to pH 9-10 with aqueous K₂CO₃ (200-300 g of 25% w/w K₂CO₃was required). The ethyl acetate layer was concentrated under vacuum toan oil which was redissolved in 1N HCl (90 mL) and washed with methylenechloride (45 mL). The aqueous layer was cooled to 2° C. Conc. (37%) HCl(9.0 mL) was added to precipitate a second crop. After stirring for 1-3hours at 2-5° C., the solid was collected by filtration and dried in avacuum oven at 55-60° C. Yield 2.1 g (12.6%).

Neutralization of Bis HCl Salt:

The bis HCl salt (10.66 g, 21.4 mmol, mixture of first and second crops)was stirred with CH₂Cl₂ (110 mL) and 5% aqueous NaHCO₃ (110 mL) untilall solids dissolved (2 hours). The aqueous layer was separated andextracted with another 50 mL CH₂Cl₂. The combined organic extracts weredried with Na₂SO₄ (10 g), filtered and concentrated under vacuum at ≦40°C. to an oil. The oil was dried on a vacuum pump to give the titlecompound as a yellow foam, 9.1 g (100%).

Alternative B

The product of Example 66F (15.0 g, 0.053 mole) was dissolved in DMF (75mL). Triisopropylborate (24.4 mL, 0.105 mole) was added and stirred atambient temperature for approximately 1.5 hours. The solution was cooledto −10° C. and a solution of5-(p-nitrophenyloxycarbonyloxymethyl)thiazole (15.0 g, 0.054 mole) inDMF (75 mL) was added over 80 minutes. The reaction was stirred forapproximately 1 hour at −10° C., then was diluted with methylenechloride (250 mL) and quenched with a mixture of triethanolamine (24.8g) and 5% aqueous sodium bicarbonate (300 mL). The biphasic mixture wasstirred for 1 hour, then the layers were separated and the aqueous wasextracted with another portion of methylene chloride (50 mL). Thecombined organic layers were extracted with 1N HCl (1×390 mL, then 1×95mL). The acid layers were combined, cooled in an ice-bath, and furtheracidified with conc. HCl (50 mL) which produced a white slurry ofproduct. The slurry was stirred for approximately 1 hour at 2° C. Thedesired product bis HCl salt) was collected by filtration and dried at55° C. in a vacuum oven. Yield 18.5 g (70%).

EXAMPLE 71 Alternative Preparation of(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

To a solution of the product of Example 70 (9.1 g, 21.4 mmol), HOBT (3.6g, 23.5 mmol) andN-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine(7.37 g, 23.5 mmol) in THF (170 mL) was added DCC (4.85 g, 23.5 mmol).The solution was stirred at ambient temperature for 16 hours (DCUprecipitates). THF was removed under vacuum and the resulting paste wasstirred with cold 1N HCl (106 mL at 5° C.) for 3 hours to dissolve thethe crude product. The DCU was removed by filtration and the filter cakewas washed with 1N HCl (30 mL). KH₂PO₄ (3.2 g) was dissolved in thecombined HCl filtrates. The solution was mixed with ethyl acetate (80mL) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w/w NaOH).The aqueous layer was extracted with another 25 mL ethyl acetate and thecombined ethyl acetate extracts were washed with aqueous NaHCO₃ (2×37 mLof 5% w/w NaHCO₃). The organic layer was dried with Na₂SO₄ (13 g),filtered, and concentrated under vacuum at ≦45° C. The residue wasdissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C. Thesolution was allowed to cool slowly and stirred overnight at roomtemperature to provide a thick slurry. The product was collected byfiltration and washed with 1:1 ethyl acetate/heptane (20 mL). Theproduct was dried briefly at 55° C. in a vacuum oven to obtain anapproximate weight prior to the second crystallization (12.85 g, 83%).

A second crystallization from 144 mL of 2:1 ethyl acetate/heptane(dissolved at −70° C., then stirred at room temperature 12 hours)produced a thick slurry of fine white solid. The product was collectedby filtration and washed with 15 mL 2:1 ethyl acetate/heptane, thendried in a vacuum oven at 55° C. for 2 days to give the desired product.Yield 11.9 g (77%).

EXAMPLE 72 Alternate Preparation of((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate EXAMPLE 72A2-Amino-5-(ethoxycarbonyl)thiazole Hydrochloride

To a −10° C. solution of potassium tert-butoxide (110 g, 0.98 mol) inTHF (1.9 L) was added a solution of ethyl chloroacetate (100 mL, 0.934mol) and ethyl formate (75 mL, 0.928 mol) in THF (400 mL) dropwise over2 hours, with good mechanical stirring. The thick solution was stirredanother 2 hours at ca. −1° C. then the reaction was quenched by additionof a solution of NaCl (150 g) in 1N HCL (750 mL). The mixture wasallowed to warm to 20° C. and the lower aqueous layer (containing someprecipitated salt) was separated. The organic layer was stripped undervacuum on a rotary evaporator. The oil was redissolved in 500 mL ethylacetate, dried with 75 g Na₂SO₄ for 1 hour, filtered and concentratedunder vacuum (40-50° C. bath temperature) to an oil. The resulting crudechloroaldehyde (161 g) and thiourea (70 g, 0.92 mol) were dissolved inTHF (2 L) and warmed to gentle reflux (60° C.). The thiourea dissolvedduring warming, and within 20 minutes, product precipitated fromsolution. After 100 minutes the suspension was allowed to cool to roomtemperature, then was cooled in an ice-bath for 1 hour. The product wascollected on a fritted Buchner funnel and washed with 2×100 mL cold THF,then dried overnight in a vacuum oven at 50° C. Yield: 122 g of titlecompound as a tan-colored solid, m.p. 182-185° C. (dec.). ¹H NMR(DMSO-d₆) δ 7.86 (s, 1H), 4.19 (q, 2H), 1.21 (t, 3H). ¹³C NMR (DMSO-d₆)δ 171.9, 160.4, 140.4, 114.4, 61.1, 14.2.

EXAMPLE 72B 2-Amino-5-(ethoxycarbonyl)thiazole

To a −10° C. solution of potassium tert-butoxide (150 g, 1.3 mol) in THF(1.35 L) was added a solution of ethyl chloroacetate (139 mL, 1.3 mol)and ethyl formate (103 mL, 1.27 mol) in THF (150 mL) dropwise over 75minutes, with good mechanical stirring. A THF rinse (25 mL) was addedover 5 minutes. The thick solution was stirred another 3 hours at ca. −5to 0° C., then the reaction was quenched by addition of a solution ofNaCl (240 g) and conc. HCl (90 mL) in water (960 mL). The mixture wasallowed to warm to 15° C. and the lower aqueous layer was discarded.Thiourea (97 g, 1.27 mol) was dissolved in the crude THF solution ofchloroaldehyde. The solution was warmed to 65° C. and refluxed for 1hour, then cooled to 30° C. Addition of a solution of K₂CO₃ (88 g, 0.64mol) in 1500 mL water produced two layers (aqueous pH=7). The THF wasremoved under vacuum at ≦45° C., causing the product to precipitate as ayellow solid. The slurry was cooled to 15° C., and the product wascollected on a fritted Buchner funnel and washed with 3×200 mL water,then dried 24 hours in a vacuum oven at 55° C. to provide 151 g of titlecompound as a yellow solid, m.p. 155-158° C.

¹H NMR (DMSO-d₆) δ 7.8 (br s, 2H, NH₂), 7.62 (s, 1H), 4.13 (q, 2H), 1.18(t, 3H). ¹³C NMR (DMSO-d₆) δ 173.4, 161.3, 147.9, 114.5, 60.1, 14.3.

EXAMPLE 72C 5-(Ethoxycarbonyl)thiazole

A solution of 2-amino-5-(ethoxycarbonyl)thiazole (50 g, 0.29 mmol) in amixture of DMF (83 mL) and THF (317 mL) was added dropwise over 87minutes to a stirred 41° C. solution of isoamyl nitrite (59 mL, 0.44mol) in DMF (130 mL). A maximum temperature of 60° C. was observedduring the exothermic addition. After another 40 minutes the THF wasremoved under vacuum at 45° C. The concentrated DMF solution was cooledto 25° C. and diluted with toluene (420 mL) and water (440 mL). Thetoluene layer was extracted with 3×120 mL water, then dried with Na₂SO₄(50 g) for 1 hour. After filtration the toluene layer was stripped on arotary evaporater at 50° C. bath temperature, then on a vacuum pump at21° C. The crude residue containing the title compound weighed 65.6 g.This material was used directly in the next step. A sample of similarlyprepared material was purified by column chromatography to give a yellowoil. ¹H NMR (CDCl₃) δ 8.95 (s, 1H), 8.51 (s, 1H), 4.39 (q, 2H), 1.40 (t,3H). ¹³C NMR (CDCl₃) δ 161.0, 157.9, 148.6, 129.8, 61.6, 14.1.

EXAMPLE 72D 5-(Hydroxymethyl)thiazole

To a slurry of lithium aluminum hydride (9.0 g) in THF (633 mL) wasadded a solution of crude 5-(ethoxycarbonyl)thiazole (65.6 g fromExample 72C) in THF (540 mL) over 95 minutes at 0-5° C. After anadditional 25 minutes, the reaction was quenched at 5° C. by sequentialaddition of water (8.1 mL), 15% NaOH (8.1 mL), and water (24.3 mL).After drying with Na₂SO₄ (44 g) for 2 hours, the slurry was filtered,and the filter cake was washed with 100 mL THF. The combined filtrateswere concentrated under vacuum at 45° C. to a brown oil (39 g). The oilwas fractionally distilled through a short-path apparatus. The productfractions distilled at 97-104° C. vapor temperature at 3-5 mm, providing20.5 g of the title compound as a turbid orange oil. ¹H NMR (CDCl₃) δ8.74 (s, 1H), 7.72 (s, 1H), 4.89 (s, 2H), 3.4 (br s, 1H, OH). 13C NMR(CDCl₃) δ 153.4, 140.0, 139.5, 56.6.

EXAMPLE 72E 5-(p-Nitrophenyoxycarbonyloxymethyl)thiazole Hydrochloride

Distilled 5-(hydroxymethyl)thiazole (14.1 g, 123 mmol) and triethylamine(17.9 mL, 129 mmol) were dissolved in ethyl acetate (141 mL) and cooledto −1° C. (ice/salt bath). A solution of 4-nitrophenyl chloroformate(26.0 g, 129 mmol) dissolved in ethyl acetate (106 mL) was addeddropwise over 50 minutes at an internal temperature of 0-4° C. An ethylacetate flask rinse (20 mL) was also added. Salts precipitated fromsolution throughout the addition. The yellow mixture was stirred another1 hour 45 minutes at 0-2° C., then a solution of dilute HCl (3.1 g, 31mmol of conc. HCl in 103 mL water) was added at once. The mixture wasstirred for 0.5 hours while warming to 15° C., then stirring wasstopped. The organic layer was washed twice with aqueous 5% K₂CO₃solution (2×70 mL), then dried with Na₂SO₄ (30 g). After filtration thesolution was concentrated under vacuum on a rotary evaporater (bathtemperature of 41° C.) to a brown oil (38 g). The crude5-(p-nitrophenyoxycarbonyloxymethyl)-thiazole was dissolved in ethylacetate (282 mL), then cooled in an ice bath to 2° C. Dry HCl gas (7.1g, 195 mmol) was bubbled in slowly over 50 minutes (temperature 2-4°C.). After stirring for another 1 hour 45 minutes at 2-4° C., the solidprecipitate was collected on a sintered glass funnel under a nitrogenblanket and the flask was washed out with 50 mL cold ethyl acetate whichwas used to rinse the filter cake. The cake was dried on the funnelunder strong nitrogen purge for 15 minutes then dried in a vacuum ovenat 50° C. with a nitrogen purge to provide 29.05 g of the title compoundas tan powder, m.p. 131-135° C. (dec.).

¹H NMR (DMSO-d₆) δ 9.21 (d, 1H), 8.27 (m, 2H), 8.06 (d, 1H), 7.52 (m,2H), 5.54 (s, 2H). ¹³C NMR (DMSO-d₆) δ 157.3, 155.2, 151.8, 145.3,143.7, 131.9, 125.5, 122.7, 62.1.

EXAMPLE 72F 5-(p-Nitrophenoxycarbonyloxymethyl)thiazole

5-(p-Nitrophenoxycarbonyloxymethyl)thiazole hydrochloride (3.0 g) wasslurried in ethyl acetate (30 mL) and cooled to 10-15° C. A solution of5% aqueous potassium carbonate (30 mL) was added with rapid stirring.After 15 minutes, stirring was stopped and the aqueous layer wasseparated. The organic layer was dried with Na₂SO₄ (3 g), filtered, andsolvent was distilled under vacuum to give 2.49 g of the title compoundas a brown syrup which slowly solidified, m.p. 62-64° C. ¹H NMR (CDCl₃)δ 8.90 (d, 1H), 8.29 (m, 2H), 8.01 (d, 1H), 7.39 (m, 2H), 5.52 (s, 2H).¹³C NMR (CDCl₃) δ 155.4, 155.2, 152.2, 145.4, 144.9, 130.6, 125.3,121.6, 61.9.

EXAMPLE 73 Alternative Preparation ofN-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineEXAMPLE 73A Thioisobutyramide

To a 1 liter three neck round bottom flask equipped with mechanicalstirrer, nitrogen atmosphere, condensor, thermocouple and 15° C. waterbath was charged (26.0 g, 0.298 mols) isobutyramide followed by (19.9 g,0.045 mols) phosphorous pentasulfide and 375 mls THF. This solution wasstirred at 20±5° C. for 3 hours, then was warmed to 60° C. and stirredan additional 3 hours. The THF was removed under vacuum with a 50° C.bath temperature to afford a yellow oil. This oil was neutralized with asolution of 5 g NaOH, 10 g NaCl and 90 g water. Next the product wasextracted into EtOAc (2×250 mls) and the combined organics reduced undervacuum to an oil. The oil was dissolved in 50 mls THF and again thesolvent was removed under vacuum to give the desired product as a yellowoil. (yield approx. 27 grams, 88%).

EXAMPLE 73B 2-Isopropyl-4-(((N-methyl)amino)methyl)thiazole

The thioisobutyramide resulting from Example 73A was dissolved in 70 mlsTHF and added slowly to a solution of (34.1 g, 0.27 mols)1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used tocompletely transfer the thioamide. The reaction was carried out in a 250ml flask with mechanical stirring under nitrogen atmosphere. Thereaction temperature was maintained below 25° C. during addition with a15±5° C. bath. The bath was kept in place for 1 hour after which it wasremoved and the reaction stirred for 18 hours. Next this stirredchloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40%aqueous methylamine solution at 15° C. in a 1 liter flask. Thetemperature was maintained below 25° C. during addition. After half anhour the bath was removed and the reaction stirred for 3 hours atambient temperature. The solvent was removed under vacuum with a 50° C.bath to an end volume of 310 mls. The residue was then basified with 50g 10% NaOH to pH 12 and extracted into methylene chloride (2×160 mls).The combined organics were then washed with 1×150 g of 20% ammoniumchloride followed by 1×90 g of 20% ammonium chloride. The combinedaqueous washes were then back extracted with 150 mls methylene chloride.The combined product methylene chloride layers were then extracted with100 g of a solution of 25 g conc. HCl and 75 g water. This acidicproduct solution was then washed with 135 mls methylene chloride. Nextthe acidic product solution was cooled, then neutralized with 100 g 20%NaOH solution. The product was extracted from this mixture withmethylene chloride (2×135 mls). The solvent was removed under vacuum toafford the desired product as an amber oil. (yield approx. 28 grams).

EXAMPLE 73CN-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valineMethyl Ester

Into a 500 ml 3-neck round bottom flask equipped with mechanicalstirrer, nitrogen atmosphere, thermocouple, heating mantle and condensorwas charged the product of Example 73B (28.1 g, 165 mols),phenoxycarbonyl-(L)-valine (41.5 g, 165 mol) and 155 ml toluene. Thissolution was warmed to reflux (110° C.) and stirred for three hours,then cooled to 20±5° C. and washed with 2×69 ml 10% citric acid followedby 1×69 ml water, 1×116 mls 4% sodium hydroxide, 1×58 ml 4% sodiumhydroxide and finally 1×58 ml water. The organic product solution wasthen treated with 3 grams of activated carbon at reflux for 15 minutes,filtered through infusorial earth to remove carbon, and thecarbon/infusorial earth cake was washed with 25 ml hot toluene. Next thesolvent was removed to afford a brown oil which solidifed upon cooling.This brown solid was dissolved with warming in 31 ml EtOAc and 257 mlheptane at 60±5° C. This solution was slowly cooled to 25° C., stirred12 hours, cooled further to 0° C., and stirred 3 hours. The crystalswere collected by filtration and washed with 50 ml 1:9 EtOAc/Heptane.The solid was dried in a 50° C. vacuum oven for 12 hours to afford 41.5grams of the desired product as a tan-colored solid (76.9%).

EXAMPLE 73DN-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine

To a one liter three neck flask was charged the product of Example 73C(50 g, 0.153 mol), lithium hydroxide monohydrate,(13 g, 0.310 mol), 200ml THF and 190 ml water. This hazy solution was stirred for 2 hours. Thereaction was quenched with a solution of conc. HCl (32.4 g, 0.329 mol)in 65 mL water, the THF was removed under vacuum and the productextracted into methylene chloride (3×210 ml). (NOTE: If necessary, thepH of the aqueous layer should be adjusted to maintain pH 1-4 during theextractions.) The combined organics were then dried with 50 g sodiumsulfate, filtered with a 150 ml methylene chloride rinse of the sodiumsulfate, and the solvent was removed under vacuum. The product wasdissolved in 450 ml THF and again the solvent was removed. Next theproduct was dissolved in 475 ml THF containing 0.12 g butylatedhydroxytoluene (BHT) for storage. If desired, the solvent can be removedunder vacuum and the residual syrup dried in a vacuum oven at 55° C. toprovide a glassy solid.

Fluorogenic Assay for Screening Inhibitors of HIV Protease

The inhibitory potency of the compounds of the invention can bedetermined by the following method.

A compound of the invention is dissolved in DMSO and a small aliquotfurther diluted with DMSO to 100 times the final concentration desiredfor testing. The reaction is carried out in a 6×50 mm tube in a totalvolume of 300 microliters. The final concentrations of the components inthe reaction buffer are: 125 mM sodium acetate, 1 M sodium chloride, 5mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 μM fluorogenicsubstrate, 2% (v/v) dimethylsulfoxide, pH 4.5. After addition ofinhibitor, the reaction mixture is placed in the fluorometer cell holderand incubated at 30° C. for several minutes. The reaction is initiatedby the addition of a small aliquot of cold HIV protease. Thefluorescence intensity (excitation 340 nM, emmision 490 nM) is recordedas a function of time. The reaction rate is determined for the first sixto eight minutes. The observed rate is directly proportional to themoles of substrate cleaved per unit time. The percent inhibition is100×(1−(rate in presence of inhibitor)/(rate in absence of inhibitor)).

Fluorogenic substrate: Dabcyl-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-EDANSwherein DABCYL=4-(4-dimethylamino-phenyl)azobenzoic acid andEDANS=5-((2-aminoethyl)amino)-naphthalene-1-sulfonic acid.

Table 1 shows the inhibitory potencies of compounds of the inventionagainst HIV-1 protease.

TABLE 1 Inhibitor Compound of Percent Concentration Example Inhibition(nanomolar) 1 79 0.5 3 70 0.5 4 72 0.5 5 79 0.5 6 75 0.5 7 74 0.5 9 640.5 10 56 0.5 11 71 0.5 12 72 0.5 13 46 0.5 14 61 0.5 15 57 0.5 17 660.5 18 80 0.5 19 70 0.5 20 86 0.5 26 71 0.5 27 82 0.5 28 68 0.5 39 630.5 41 75 0.5 42 70 0.5 44 68 0.5 45 50 0.5 46 46 0.5 47 73 0.5 48 690.5 49 55 0.5 50 61 0.5 51 69 0.5 52 71 0.5 53 75 0.5 54 50 0.5 55 540.5 56 66 0.5 57 64 0.5 58 49 0.5 59 39 0.5 60 44 0.5 61 69 0.5 62 540.5 63 61 0.5 64 52 0.5 65 70 0.5

Antiviral Activity

The anti-HIV activity of the compounds of the invention can bedetermined in MT4 cells according to the procedure of Kempf, et. al.(Antimicrob. Agents Chemother. 1991, 35, 2209). The IC₅₀ is theconcentration of compound that gives 50% inhibition of the cytopathiceffect of HIV. The LC₅₀ is the concentration of compound at which 50% ofthe cells remain viable.

Table 2 shows the inhibitory potencies of compounds of the inventionagainst HIV-1 _(3B) in MT4 cells.

TABLE 2 Compound of IC₅₀ LC₅₀ Example (micromolar) (micromolar) 10.025-0.040 55 3 0.041-0.075 52 4 0.17-0.32 29 5 0.003-0.009 51 60.006-0.014 100 7 0.076-0.131 56 8 0.057-0.095 97 9 0.080-0.10  62 100.054-0.071 55 11 0.017-0.132 60 12 0.053-0.106 >100 13 0.056-0.088 5614 0.14-0.22 >100 15 0.43-0.67 41 17 0.23-0.31 19 18 0.039-0.046 62 190.022-0.048 87 20 0.011-0.014 55 26 0.007-0.011 28 27 0.011-0.012 57 280.11-0.12 18 39 0.073-0.077 22 41 0.015-0.02  100 42 0.073-0.08  >100 440.12-0.16 19 45 0.036-0.040 19 46 0.10-0.17 61 47 0.009-0.024 25 480.09-0.11 >100 49 0.081-0.13  38 50 0.15-0.27 >100 51 0.045-0.049 45 520.035-0.042 26 53 0.032-0.073 59 54 0.11-0.17 19 55 0.14-0.22 17 56 0.05-0.067 100 57 0.035-0.048 >100 58  0.03-0.046 18 59 0.11-0.13 18 600.34-0.51 17 61 0.15-0.22 25 62 0.69-1.0  17 63 0.13-0.18 45 640.10-0.13 >100 65 0.12-0.20 >100

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, bezenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Othersalts include salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases.

Preferred salts of the compounds of the invention include hydrochloride,methanesulfonate, sulfonate, phosphonate and isethionate.

The compounds of the present invention can also be used in the form ofesters. Examples of such esters include a hydroxyl-substituted compoundof formula A or A1 or A2 which has been acylated with a blocked orunblocked amino acid residue, a phosphate function, a hemisuccinateresidue, an acyl residue of the formula R*C(O)— or R*C(S)— wherein R* ishydrogen, loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl,thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formulaR_(a)—C(R_(b))(R_(d))—C(O)— or R_(a)—C(R_(b))(R_(d))—C(S)— wherein R_(b)and R_(d) are independently selected from hydrogen or loweralkyl andR_(a) is —N(R_(e))(R_(f)), OR_(e) or —SR_(e) wherein R_(e) and R_(f) areindependently selected from hydrogen, loweralkyl and haloalkyl, or anamino-acyl residue of the formula R₁₈₀NH(CH₂)₂NHCH₂C(O)— orR₁₈₀NH(CH₂)₂OCH₂C(O)— wherein R₁₈₀ is hydrogen, loweralkyl, arylalkyl,cycloalkylalkyl, alkanoyl, benzoyl or an a-amino acyl group. The aminoacid esters of particular interest are glycine and lysine; however,other amino acid residues can also be used, including those wherein theamino acyl group is —C(O)CH₂NR₂₀₀R₂₀₁ wherein R₂₀₀ and R₂₀₁ areindependently selected from hydrogen and loweralkyl or the group—NR₂₀₀R₂₀₁ forms a nitrogen containing heterocyclic ring. These estersserve as pro-drugs of the compounds of the present invention and serveto increase the solubility of these substances in the gastrointestinaltract. These esters also serve to increase solubility for intravenousadministration of the compounds. Other prodrugs include ahydroxyl-substituted compound of formula A or A1 or A2 wherein thehydroxyl group is functionalized with a substituent of the formula—CH(R_(g))OC(O)R₁₈₁ or —CH(R_(g))OC(S)R₁₈₁ wherein R₁₈₁ is loweralkyl,haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R_(g) is hydrogen,loweralkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonylor dialkylaminocarbonyl. Such prodrugs can be prepared according to theprocedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysisof the corresponding methallyl ether in methanol followed by treatmentwith acetic anhydride.

The prodrugs of this invention are metabolized in v to provide thehydroxyl-substituted compound of formula A or A1 or A2. The preparationof the prodrug esters is carried out by reacting a hydroxyl-substitutedcompound of formula A or A1 or A2 with an activated amino acyl,phosphoryl, hemisuccinyl or acyl derivative as defined above. Theresulting product is then deprotected to provide the desired pro-drugester. Prodrugs of the invention can also be prepared by alkylation ofthe hydroxyl group with (haloalkyl)esters, transacetalization withbis-(alkanoyl)acetals or condensation of the hydroxyl group with anactivated aldehyde followed by acylation of the intermediate hemiacetal.

The compounds of the invention are useful for inhibiting retroviralprotease, in particular HIV protease, in vitro or in vivo (especially inmammals and in particular in humans). The compounds of the presentinvention are also useful for the inhibition of retroviruses in vivo,especially human immunodeficiency virus (HIV). The compounds of thepresent invention are also useful for the treatment or prophylaxis ofdiseases caused by retroviruses, especially acquired immune deficiencysyndrome or an HIV infection in a human or other mammal.

Total daily dose administered to a human or other mammal host in singleor divided doses may be in amounts, for example, from 0.001 to 300 mg/kgbody weight daily and more usually 0.1 to 10 mg. Dosage unitcompositions may contain such amounts of submultiples thereof to make upthe daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

The compounds of the present invention may be administered orally,parenterally, sublingually, by inhalation spray, rectally, or topicallyin dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifylng and suspending agents, and sweetening, flavoring, andperfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologically aceptableand metabolizable lipid capabale of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natureal and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

One preferred dosage form for the compounds of the invention comprises asolid dosage form for oral administration comprising a pharmaceuticallyacceptable adsorbent to which is adsorbed a mixture of (1) apharmaceutically acceptable organic solvent or a mixture of two or morepharmaceutically acceptable organic solvents, (2) a compound of theinvention in the amount of from about 10% to about 40% by weight and (3)a total of from about 0.2 molar equivalents to about 2 molar equivalents(based on the compound of the invention) of a pharmaceuticallyacceptable acid.

This composition is filled into hard gelatin capsules foradministration. The preparation of a specific example of this type ofdosage form is described below.

Solid-filled Capsule Dosage Form Preparation

Propylene glycol (USP, 139 mL) and ethanol (dehydrated, USP, 200 proof,139 mL) were mixed in a stainless steel or glass container. Hydrochloricacid (reagent grade, 20 mL) was added and mixed well. To this solutionwas added ascorbic acid (21 g) and the mixture was stirred until it wasclear. The product of Example 1U (200 g) was slowly added to thesolution and mixing was continued until the solution was clear.Cremophore® EL (polyoxyethyleneglycerol oxystearate, 41 g) andpolysorbate 80, NF (41 g) were added with mixing.

Microcrystalline cellulose, NF (139 g) and silicon dioxide, NF (Syloid244, pharmaceutical grade, 209 g) were charged into a Hobart mixer andmixed for 3-5 minutes. The above solution was added dropwise to the drymixture in the Hobart mixer while mixing at slow speed. This mixture wasmassed until granular.

The wet granulation was screened through an 8 mesh screen. The screenedgranulation was spread on paper-lined trays and dried in a tray dryer ora fluidbed dryer (20-35° C.) until the loss on drying was not more than12%.

The concentration of the product of Example 1U (mg/g of granulation) inthe granulation was determined by HPLC analysis. Capsules (gelatin, No.00, iron gray opaque) were filled with the appropriate amount of thedried granulation to provide the desired dose per capsule.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents, other antiinfectiveagents or vaccines. Other antiviral agents to be administered incombination with a compound of the present invention include AL-721,beta interferon, polymannoacetate, reverse transcriptase inhibitors (forexample, dideoxycytidine (DDC), dideoxylnosine (DDI), BCH-189, AzdU,carbovir, DDA, D4C, D4T, DP-AZT, FLT (fluorothymidine),BCH-189,5-halo-3′-thiadideoxycytidine, PMEA, zidovudine (AZT) and thelike), non-nucleoside reverse transcriptase inhibitors (for example, R82193, L-697,661, BI-RG-587 (nevirapine), retroviral protease inhibitors(for example, HIV protease inhibitors such as Ro 31-8959, SC-52151,KNI-227, KNI-272 and the like), HEPT compounds, L,697,639, R82150,U-87201 E and the like), TAT inhibitors (for example, RO-24-7429 and thelike), trisodium phosphonoformate, HPA-23, eflonithine, Peptide T,Reticulose (nucleophosphoprotein), ansamycin LM 427, trimetrexate,UA001, ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G,cyclobut-A, ara-M, BW882C87, foscarnet, BW256U87, BW348U87, L-693,989,BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109,TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir,ganciclovir, castanospermine, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ,hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate.Immunomodulators that can be administered in combination with a compoundof the present invention include. bropirimine, Ampligen, anti-humanalpha interferon antibody, colony stimulting factor, CL246,738, Imreg-1,Imreg-2, diethydithiocarbamate, interleukin-2, alpha-interferon, inosinepranobex, methionine enkephalin, muramyl-tripeptide, TP-5,erythropoietin, naltrexone, tumor necrosis facator, beta interferon,gamma interferon, interleukin-3, interleukin-4, autologous CD8+infusion, alpha interferon immunoglobulin, IGF-1, anti-Leu-3A,autovaccination, biostimulation, extracorporeal photophoresis, FK-565,FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG, HIVIG, passiveimmunotherapy and polio vaccine hyperimmunization. Other antiinfectiveagents that can be administered in combination with a compound of thepresent invention include pentamidine isethionate. Any of a variety ofHIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120),HIVAC-1e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag(gp160), HGP-30, HIV-Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24)can be used in combination with a compound of the present invention.Other agents that can be used in combination with the compounds of thisinvention are ansamycin LM 427, apurinic acid, ABPP, AI-721, carrisyn,AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-acetylcysteine, (2-oxothiazolidine-4-carboxylate), D-penicillamine,diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23,human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or otherquinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin,MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng,pentofylline, pentoxifylline, Peptide T, pine cone extract,polymannoacetate, reticulose, retrogen, ribavirin, ribozymes, RS-47,Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin,thymosin fraction 5, thymosin alpha one, thymostimulin, UA001, uridine,vitamin B12 and wobemugos.

Other agents that can be used in combination with the compounds of thisinvention are antifungals such as amphotericin B, clotrimazole,.flucytosine, fluconazole, itraconazole, ketoconazole and nystatin andthe like.

Other agents that can be used in combination with the compounds of thisinvention are antibacterials such as amikacin sulfate, azithromycin,ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol,isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65and the like.

Other agents that can be used in combination with the compounds of thisinvention are anti-neoplastics such as alpha interferon, COMP(cyclophosphamide, vincristine, methotrexate and prednisone), etoposide,mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide,vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate(w/leucovin rescue), doxorubicin, cyclophosphamide,etoposide/mechlorethamine, vincristine, prednisone and procarbazine),vincristine, vinblastine, angioinhibins, pentosan polysulfate, plateletfactor 4 and SP-PG and the like.

Other agents that can be used in combination with the compounds of thisinvention are drugs for treating neurological disease such as peptide T,ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparinand cytosine arabinoside and the like.

Other agents that can be used in combination with the compounds of thisinvention are anti-protozoals such as albendazole, azithromycin,clarithromycin, clindamycin, corticosteroids, dapsone, DIMP,eflornithine, 566C80, fansidar, furazolidone, L,671,329, letrazuril,metronidazole, paromycin, pefloxacin, pentamidine, piritrexim,primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine,trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.

Among the preferred agents for treatment of HIV or AIDS in combinationwith the compounds of this invention are reverse transcriptaseinhibitors.

It will be understood that agents which can be combined with thecompounds of the present invention for the treatment or prophylaxis ofAIDS or an HIV infection are not limited to those listed above, butinclude in principle any agents useful for the treatment or prophylaxisof AIDS or an HIV infection.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A process for the preparation of a compound of the formula:

or an N-protected derivative thereof; wherein R₄ and R_(4a) are independently selected from phenyl, thiazolyl and oxazolyl wherein the phenyl, thiazolyl and oxazolyl ring is unsubstituted or substituted with a substituent selected from the group consisting of (i) halo, (ii) loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy; R₆ is hydrogen or loweralkyl; and R₇ is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein the thiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted or substituted with loweralkyl, comprising reacting a compound of the formula:

or an N-protected derivative thereof wherein R_(4a) and R₄ are as defined above with an acylating compound of the formula:

wherein R₆ and R₇ are as defined above; and L is an activating group for an acylation reaction.
 2. The process of claim 1 wherein R_(4a) and R₄ are phenyl, R₆ is hydrogen and R₇ is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl.
 3. The process of claim 1 wherein R_(4a) and R₄ are phenyl, R₆ is hydrogen and R₇ is thiazolyl.
 4. The process of claim 1 wherein wherein L is p-nitrophenyl, phenyl, N-succinimidyl, N-phthalimidyl, N-benzotriazolyl, N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl.
 5. A process for the preparation of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane or an N-protected derivative thereof, comprising reacting (2S,3S,5S)— 2,5-diamino-1,6-diphenyl-3-hydroxyhexane or an N-protected derivative thereof with an acylating compound of the formula:

wherein L is an activating group for the acylation reaction.
 6. The process of claim 5 wherein L is p-nitrophenyl, phenyl, N-succinimidyl, N-phthalimidyl, N-benzotriazolyl, N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl.
 7. The process of claim 5 wherein L is p-nitrophenyl.
 8. The process of claim 5 wherein L is phenyl.
 9. The process of claim 5 wherein L is N-succinimidyl.
 10. The process of claim 5 wherein L is N-phthalimidyl.
 11. The process of claim 5 wherein L is N-benzotriazolyl.
 12. The process of claim 5 wherein L is N-5-norbornene-2,3-carboxamidyl.
 13. The process of claim 5 wherein L is 2,4,5-trichlorophenyl.
 14. A process for the preparation of (2S,3S,5S)-5-(t-butyloxycarbonylamino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, comprising reacting (2S,3S,5S)— 2-amino-5-(t-butyloxycarbonylamino)-1,6-diphenyl-3-hydroxyhexane with an acylating compound of the formula:

wherein L is an activating group for the acylation reaction.
 15. The process of claim 14 wherein L is p-nitrophenyl, phenyl, N-succinimidyl, N-phthalimidyl, N-benzotriazolyl, N-5-norbornene-2,3-carboxamidyl or 2,4,5-trichlorophenyl.
 16. The process of claim 14 wherein L is p-nitrophenyl.
 17. The process of claim 14 wherein L is phenyl.
 18. The process of claim 14 wherein L is N-succinimidyl.
 19. The process of claim 14 wherein L is N-phthalimidyl.
 20. The process of claim 14 wherein L is N-benzotriazolyl.
 21. The process of claim 14 wherein L is N-5-norbornene-2,3-carboxamidyl.
 22. The process of claim 14 wherein L is 2,4,5-trichlorophenyl.
 23. (2S,3S,5S)-5-(t-butyloxycarbonylamino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane. 